Materiały źródłowe

• #1 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9139759/

  Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. […] Treatment strategies vary depending on the molecular subtype. Breast cancer treatment is multidisciplinary; it includes approaches to locoregional therapy (surgery and radiation therapy) and systemic therapy. Systemic therapies include hormone therapy for hormone-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, and quite recently, immunotherapy. Triple negative breast cancer is responsible for more than 15-20% of all breast cancers. It is of particular research interest as it presents a therapeutic challenge, mainly due to its low response to treatment and its highly invasive nature. Future therapeutic concepts for breast cancer aim to individualize therapy and de-escalate and escalate treatment based on cancer biology and early response to therapy.

• #1 Breast Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482286/

  Breast cancer most commonly arises in the ductal epithelium (ie, ductal carcinoma) but can also develop in the breast lobules (ie, lobular carcinoma). […] Most breast cancer is sporadic (90%-95%), with only 5% to 10% of patients having an identifiable genetic mutation. […] Carcinogenesis occurs due to a complex interplay of genetic and environmental risk factors, hormonal influences, and patient-related factors. […] The pathogenesis, treatment, and prognosis are closely associated with the following molecular subtypes of breast cancer: […] Hormone receptor-positive tumors (ie, luminal A and B) tend to be less aggressive, with improved survival rates. […] HER-2 enriched tumors are more aggressive, with a poor prognosis without targeted therapy. […] Basal-like tumors are negative for the molecular markers and tend to have a worse prognosis with poor survival rates.

• #1 Breast cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/breast-cancer/symptoms-causes/syc-20352470

  Breast cancer is a kind of cancer that begins as a growth of cells in the breast tissue. […] Healthcare professionals know that breast cancer starts when something changes the DNA inside cells in the breast tissue. A cell’s DNA holds the instructions that tell a cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells. […] The DNA changes that lead to breast cancer most often happen in the cells that line the milk ducts. These ducts are tubes designed to carry milk to the nipple. Breast cancer that starts in the ducts is called invasive ductal carcinoma. Breast cancer also can start in cells in the milk glands. These glands, called lobules, are designed to make breast milk. Cancer that happens in the lobules is called invasive lobular carcinoma. Other cells in the breast can become cancer cells, though this isn’t common.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Breast-Cancer-Pathophysiology.aspx

  Breast cancer is a malignant tumor that starts in the cells of the breast. Like other cancers, there are several factors that can raise the risk of getting breast cancer. Damage to the DNA and genetic mutations can lead to breast cancer have been experimentally linked to estrogen exposure. Some individuals inherit defects in the DNA and genes like the BRCA1, BRCA2 and P53 among others. Those with a family history of ovarian or breast cancer thus are at an increased risk of breast cancer. […] The immune system normally seeks out cancer cells and cells with damaged DNA and destroys them. Breast cancer may be a result of failure of such an effective immune defence and surveillance. […] These are several signalling systems of growth factors and other mediators that interact between stromal cells and epithelial cells. Disrupting these may lead to breast cancer as well.

• #1 Breast cancer – McMaster Pathophysiology Review

  https://www.pathophys.org/breast-cancer/

  Two major hypotheses attempt to explain the tumorigenic effects of estrogen: (i) genotoxic effects of estrogen metabolites via generation of radicals (initiator) and (ii) the hormonal properties of estrogen inducing proliferation of cancers as well as the premalignant cells (promoter). […] HER2 belongs to the epidermal growth factor receptor (EGFR) family of proto-oncogenes and currently is not known to have a ligand. However, the protein has been shown to form clusters within the cell membranes in malignant breast tumours. Its mechanism of carcinogenesis remains largely unknown, but overexpression is associated with rapid tumour growth, shortened survival, increased risk of recurrence after surgery, and poor response to conventional chemotherapeutic agents. […] Breast cancer is a hormone-sensitive cancer. Most breast cancer cells are ER-positive, and thus will respond to reduction of circulating estrogens. HR-negative breast cancers will not respond to endocrine therapy.

• #1 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://www.mdpi.com/2072-6694/14/10/2569

  Estrogens play an important role in the pathogenesis of the development of breast cancer. Breast cancer is considered a hormone-dependent tumor in which elevated estrogen levels and longer exposure to this hormone are associated with an increased risk of its development. […] The presence of mutations in these genes occurs only in 3–5% of breast cancer patients. However, due to the high penetration of BRCA1/BRCA2 genes, these patients should be included in the prophylactic program. […] The use of HRT is a significant risk factor for breast cancer. […] The relationship between hormonal contraceptive use and breast cancer risk has been demonstrated in two important papers—a reanalysis of 54 epidemiological studies by the Collaborative Group on Hormonal Factors in Breast Cancer published in The Lancet in 1996, and a prospective cohort study by Mørch et al. presented in the NEJM in 2017.

• #1 Breast cancer – McMaster Pathophysiology Review

  https://www.pathophys.org/breast-cancer/

  Breast cancer requires a hormonal supply to develop, much like the tissue it arises out of. Risk of breast cancer increases with lifetime estrogen exposure. The majority of breast cancers are hormone sensitive, meaning that they express estrogen receptors and proliferate in response to estrogen stimulation. Endocrine therapies that inhibit estrogen production are effective in treating hormone-sensitive breast cancer. […] Two different types of estrogen receptors exist, alpha and beta (ER and ER respectively). Various tissues express these receptors with breast, ovaries and the endometrium expressing ER, while the kidneys, brain, lungs and several other organs expressing ER. The role of ER in carcinogenesis remains controversial whereas, a clear contribution of ER protein has been established.

• #1 Unifying mechanism in the initiation of breast cancer by metabolism of estrogen (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6738

  Excessive exposure to estrogen is associated with increased risk of breast cancer. The mechanisms of carcinogenesis in the breast caused by estrogen metabolism include formation of depurinating adducts which are released from DNA to generate apurinic sites, and production of reactive oxygen species (ROS). […] Estrogens have been implicated in the etiology of breast cancer. Epidemiological and clinical evidence has indicated that factors associated with elevated estrogen levels throughout the lifetime of a female, including the early onset of menstruation, late menopause, use of oral contraceptives, late first full-term pregnancy, and hormone replacement therapy, are associated with an increase in breast cancer risk among pre- and postmenopausal women. […] Compared with ER-mediated processes, substantial evidence suggests that the oxidative metabolism of estrogens serves a major role in the initiation of breast cancer. Specific estrogen metabolites, predominantly catechol estrogens-3,4-quinones (CE-3,4-Q), have the potential to initiate the cancer process by binding to DNA and forming depurinating adducts, 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua.

• #1 Unifying mechanism in the initiation of breast cancer by metabolism of estrogen (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6738

  The greater carcinogenic activity of 4-OHE1(E2) is associated with a higher amount of depurinating DNA adducts formed by E1(E2)-3,4-Q, compared with E1(E2)-2,3-Q. […] Accumulating evidence for the initiation of cancer by estrogen-DNA adducts has been identified by using human breast epithelial cell lines such as MCF-10F, which is an immortalized, non-transformed ER-a-negative cell line. […] The results further indicate that transformation occurs via the genotoxic effects of the estrogen metabolites. […] The mutagenicity of E1(E2)-3,4-Q was first studied in female SENCAR mice by determining the H-ras mutations induced, and the estrogen-DNA adducts formed. […] High levels of estrogen-DNA adducts have been seen in analyses of urine and serum from women that are at high risk of breast cancer.

• #1 Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NFκβ interplay | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-020-1153-y

  Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NF interplay. Estrogen sulfotransferase catalyzes conjugation of sulfuryl-group to estradiol/estrone and regulates E2 availability/activity via estrogen-receptor or non-receptor mediated pathways. High estrogen is a known carcinogen in postmenopausal women. Reports reveal a potential redox-regulation of hSULT1E1/E2-signalling. Oxidative-stress induces SULT1E1 via Nrf2/NF cooperatively in tumor-pathogenesis to maintain the required proliferative-state under enriched E2-environment. SULT1E1 expression and E2-level were increased in tumor-tissue compared to their corresponding surrounding-tissues. It may be concluded that tumors maintain a sustainable oxidative-stress through impaired antioxidants as compared to the surrounding. Estrogen has been regarded as one of the most effective cause in breast cancer. Both endogenous and exogenous estrogen has been already declared as human carcinogen in pre and post-menopausal women. This suggests that E2 may also function at cellular and molecular level via estrogen receptor (ER) independent pathway. So, beside ER involvement, E2 level alone can be a potent determinant of cellular transformation. Studies report that one-fourth of breast cancer patients carrying BRCA1 mutation were ER+ by nature. These data suggest that estrogen is the most important factor in breast cancer initiation and progression. Monitoring and targeting estrogen synthesizing and regulatory protein may control estrogen malfunction. Studies report that sulfonated estrogens have no ER binding affinity whereas desulfation of estrogen sulfates may contribute to high levels of active estrogen in target tissues. In this regard, estrogen sulfotransferase (SULT1E1), an important member of the of steroid-sulfotransferases super family, sulfonate estrogen into biologically inactive estrogen sulfates. A correlation between SULT1E1 and the carcinogenesis of estrogen-dependent cancers has been noticed. This is important that the level of SULT1E1 expression is inversely correlated with malignancy in breast cancers. Induction of intra-tumoral SULT1E1 and reduction of estrogen concentration by TM208 contributes to the anti-breast cancer action. The redox environment is associated with breast cancer pathogenesis and metastasis. And in this process roles of oxidatively-regulated nuclear-receptor-factor 2 (Nrf2) which is also a regulator of SULT1E1 and nuclear factor kappa-light-chain-enhancer of activated cells (NF) have been investigated. The current manuscript clearly shows the redox regulation of SULT1E1 and other radical-metabolizing enzymes in the pathogenesis of human breast cancer of different stages. This redox regulation is demonstrated to be related to intracellular level of oxidant stress and related gene expressions like Nrf2 and NF. Breast cancer may depend on both genetic and hormonal factors. Epidemiologic and experimental data infers that mainly estradiol (E2) plays a pivotal role in the development and progression of breast cancers by promoting cell proliferation via ER signalling. It initiates mutations that occur as a function of errors during DNA replication. E2 harbours significant number of mutations, ultimately resulting in cancers. Receptor independent effects of E2 may also be involved in the breast carcinogenesis. In animal models E2-administration and in human E2-therapy causes breast cancer which may be prevented by the anti-estrogenic drugs tamoxifen or raloxifene. This might be possible due to altered metabolism of E2 and direct effect of E2-induced stress. Our earlier study showed that E2 administration to human tumor xenografted rat impaired SULT1E1 protein/mRNA expression resulting higher plasma E2 level. Anti-estrogens and other cancer therapeutic drugs have been shown to alter SULT1E1 protein/gene expressions and E2 signalling rate. This suggests that regulations of SULTs have great implications in E2 function. In the current study, the presence of higher in situ estradiol infers either its increased rate of synthesis or its high rate of accumulation in the circulation. It is reported that cellular uptake of estrogen metabolites (E1S) takes place by human organic anion transporting polypeptide 1A2 (OATP1A2) which is up-regulated by the elevated expression of pregnane X receptor (PXR) in malignant tissue. So, strategies to minimize estrogen activities are proved effective measure to treat breast cancers. Earlier reports hypothesise that, women with mutations in estrogen metabolizing enzymes are expected to develop breast cancer. This suggests a major role of estrogen metabolizing enzymes like aromatase, sulfatase, 17-HSD and SULT1E1 in breast cancer. SULT1E1 acts at nanomolar concentration of estradiol and SULT1A1 acts at micromolar concentrations of (E2). So, SULT1E1 can inactivate most of this hormone present. Expression of SULT1E1 in MCF-7 cells reduced the response to physiologic concentrations of estradiol and inhibited estrogen-stimulated DNA synthesis and cell proliferation. Elevated E2 level in the tumor suggest that SULT1E1 expression is not sufficiently enough for E2 inactivation. In-situ inactivation of E2 is possible by SULT1E1 induction and it may be a way to decrease breast cancer risk. In our study, an increased SULT1E1 expression is noticed in breast tumor samples as compared to their corresponding surrounding tissue and comparatively low in some tumors resulting poor prognosis. Tumor expression of SULT1E1 was also found to be positively correlated with ER- and PR-B, which are associated with an improve prognosis for breast cancer. Studies also report that over-expression of SULT1E1 inhibits proliferation, induce cell apoptosis, suppress angiogenesis, arrest cell cycle in vitro and tumorigenesis in vivo. And this protective function of SULT1E1 was associated with increase in expressions of MMP-2 and MMP-9 in MCF-7 cell based xenograft mouse. Earlier reports from our lab suggested a potential redox regulation of hSULT1E1 through Cys83 modification. It is of worth notify that even in higher SULT1E1 condition adverse response from other stress regulated gene i.e., HIF1, NF may also promote the disease. Estrogens are converted into catechol estrogens and during this process ROS are produced. Estrogen quinones are conjugated with glutathione (GSH) both in vivo and in vitro by glutathione transferases which results in high level of DNA protection. In our studies elevated NPSH in tumors compared to corresponding surrounding suggests a possibility of thiol conjugation of estrogen metabolites and protecting tumor cells from ROS/drug induced DNA damage. The increase of malondialdehyde in the tumor than their corresponding surrounding tissues interprets a high rate of lipid peroxidation resulting from free radicals/H2O2 and oxidative stress. In human breast cancer cells, extracellular signal-regulated kinase (Erk1/2) which was activated by H2O2 generated as a by-product during estrogen metabolism increases cell proliferation. Recent data suggest that H2O2 may cross cellular membranes through specific members of the aquaporin family. ROS generation during estrogen metabolism or other potential mammary carcinogenic factors as evident from MDA results was shown to activate the PI3K/Akt signalling pathway. Serine/threonine-specific protein kinase (Akt) activation generates the anti-apoptotic and anti-inflammatory responses in tumor cells, thereby protecting it from drug induced apoptosis or inflammatory apoptosis. The elevated NPSH in tumors increases intracellular redox potential and an adaptive protective strategy against ROS dependent inhibitory (apoptotic) signalling. Imbalance in glutathione system induces programmed cell death in tumors. Elevated NPSH supported increased SOD activity in the tumors as compared to their corresponding surrounding tissue. This causes a quick conversion of superoxide into H2O2 and facilitating tumors with low superoxide. Activity of catalase was variable in tumors and surrounding. Catalase over-expression (CAT3 cells) increased the resistance of cancer cells to drugs inducing oxidative stress, likely by increasing the antioxidant status of cancer cells. Hydroxyl radical attack DNA rapidly due to their high infusibility which results in formation of DNA lesions including oxidized DNA bases, single strand and double strand breaks. These can be novel supporting therapeutic strategies. Low doses of hydrogen peroxide and superoxide stimulate cell proliferation in a wide variety of cancer cell types which is evident from our study where SOD and catalase activity are highly favouring to cancer cells with low oxidative stress. Increased generation of hydrogen peroxide drives the proliferating cells to transit into quiescence. Increased expression of a variety of enzymes like SOD, Cat and GPx that contribute to oxygen radical scavenging favours disease pathogenesis by inhibiting the pro-oxidant effect of drugs. To verify whether redox regulation of antioxidant enzyme is possible or not, human RBC membrane enzymes were analysed. Since, RBC contains very high level of antioxidant enzymes against ROS. SOD, CAT and GPx were incubated with different concentration of H2O2 and -ME alone or together. It was noticed that both SOD and CAT activity were reduced in the presence of H2O2 while the activity was increased by the reducing equivalent like -ME. A similar scenario may be evident in the in vivo condition in tumor tissues compared to that of their surrounding tissue. The increased SOD, Cat and GPx activity may be favoured by the elevated NPSH in vivo condition which reduces back the enzymatic catalytic sites. Giving insights that redox modulation by SH crucially induced modification of antioxidant enzymes activity and favours to maintain a low level of ROS which may activate anti-apoptotic protein Akt. In breast cancer cells, inhibition of the mitochondrial ROS generation suppresses estrogen induced cell proliferation, proposing a role of estrogen mediated mitochondrial ROS in tumor growth. After malignant transformation many cancer cells show a sustained increase in intrinsic reactive oxygen species which maintains the oncogenic phenotype and drives tumor progression. Conclusively, redox adaption through up regulation of anti-apoptotic and antioxidant molecules allows cancer cells to promote survival and to develop resistance to anticancer drugs. Little is known how an increase in intracellular oxidative stress levels is sensed and transduced into ROS-induced specific intracellular signalling to regulate the expression of antioxidant and survival genes. In spite of the extensive biochemical characterization and functional studies of SULT1E1 until recently, little is known about the transcriptional regulation of SULT1E1 under oxidative stress. In our study, SULT1E1 is contrarily expressed in breast cancer patients along with an increased oxidative stress in both the surrounding and tumor. A study reports that SULT1E1 is the transcriptional target of nuclear receptor factor 2 (Nrf2). Nrf2 remains low under normal conditions but it is induced many-fold in response to endogenous or exogenous stresses or toxicants. Nrf2 target genes function in elimination of reactive oxygen species (ROS) and diminishing inflammation, drug and carcinogen detoxication, and intermediary metabolism. According to the immunohistochemistry results Nrf2 was significantly more in the tumor tissue as compared to the corresponding surrounding. It indicates that Nrf2 may be the transcriptional regulator of SULT1E1 in case of breast cancers. Our correlation study strongly supports this finding. Keap1 negatively regulates Nrf2 by targeting it for subsequent degradation. A study presents evidence that Dipeptide-peptidase 3 (DPP3) binding sequesters KEAP1 in an oxidative stress-inducible manner and enhances the Nrf2 function. Elevated levels of DPP3 mRNA correlate with increased Nrf2 downstream gene expression. Nrf2 has emerged as a key modifier in cancer development, acting in both tumor suppression and tumor promotion functions, depending on context. High levels of Nrf2 in tumors are generally correlated with poor prognosis. SULT1E1 is expressed under oxidative stress as evident from our MDA results, where Nrf2 is activated. Eventually, that favours Nrf-2 function which may induce SULT1E1. Another way is that oxidative stress blocks the E3 ligase activity of Keap1 which stabilizes Nrf2 allowing it to drive the expression of certain antioxidant and drug metabolizing enzyme as noticed in the current study. Thus, oxidative stress favours the Nrf2 pathway of SULT1E1 up-regulation. Breast tumors NPSH level may provide a localized reducing environment where active Keap1 may negatively regulate Nrf2 and hinders the SULT1E1 expression as in few patients. On the other hand dexamethasone (DEX) induced the expression and activity of SULT1E1 through glucocorticoid receptor (GR). Functional activity of the GR is suppressed under oxidative conditions and restored in the presence of reducing reagents. The GR pathway of SULT1E1 induction is suppressed under oxidative stress. It is likely to be a state where GR pathway and Nrf-2 (if keap1 is not mutated in breast cancer) both remain suppressed under oxidative stress, as may be the case of low SULT1E1 expression in a few breast tumors. It may be proposed that expression/function of oxidative stress regulated SULT1E1 cannot rely on unidirectional pathways, rather complex and pivotal switching machinery regulates its action. In an in vitro experiment we found that dexamethasone, a glucocorticoid receptor (GR) activator causes induction of SULT1E1 which helps antagonizing E2. In an in vivo xenografted-E2 model SULT1E1 expression was significantly reduced compared to control. This indicates that excess E2 regulates its availability via SULT1E1 inhibition. Thus antagonising E2 may not allow E2 to impose its regulatory effect on SULT1E1 expression. Activation of GR induces SULT1E1 which may be an essential pathway in breast cancer patients where GR is influenced by oxidative stress. To strongly confirm whether Nrf2 is responsible for SULT1E1 expression we also did an in vitro experiment with lansoprazole, a known Nrf2 inducer. Lansoprazole a potent gastric ulcer drug which inhibits proton pump induces anti-oxidative stress via induction of Nrf2. The cells incubated with lansoprazole showed an elevated SULT1E1. Thus, confirming the fact that Nrf2 causes induction of SULT1E1. This study evidently proofs that the variation in Nrf2 expression and activation as a transcription factor may play an important role in breast cancer patients via induction of SULT1E1 what we have noticed in our immunohistochemical study. A report showed that aryl hydrocarbon receptor (AhR) knockdown significantly increased SULT1E1 expression. When the breast cells switch to a proliferative state, a lessening of cell-cell contact causes activation of AhR activity and suppression of SULT1E1 expression in tumor as found in our studies, resulting in increased active estrogen levels in the breast microenvironment. Interestingly it was found that arsenic-induced AhR activation and -enhanced CYP1A1 expression can be further increased by a pro-oxidant, buthionine-(S,R)-sulfoximine, and suppressed by antioxidants, such as N-acetylcysteine and catalase leading to the conclusion that AhR is active under oxidative stress which may suppress SULT1E1 expression. To support the above interpretations, we treated female rats only with E2 and found that SULT1E1 expression was decreased both at mRNA and protein level as compared to the control. At the same time induction of NPSH and reduction of MDA (oxidative stress marker) were noticed. Proposing that local redox environment may regulate SULT1E1 expression. Perhaps tumors expressed SULT1E1 mRNA more than the surrounding, and SULT1E1 protein was high in few tumors and low in some as compared to that of the surrounding. The average E2 level was high in tumors along with high MDA. Thus, two different pathways are likely to be controlling the SULT1E1 expression, one via E2 and the other via oxidative stress and both resulted in the carcinogenic transformation of the tissues. A delicate intracellular interplay between oxidizing and reducing equivalents allows ROS and E2 to function as second messengers in the control of cell proliferation and transformation. Estrogen via ER induces transcriptional activation of E2F1 which results in the tamoxifen resistance in breast cancer cells. ER status is not the major determinant of breast cancer progression via estrogen. A summated effect of estrogen and oxidative stress is responsible for breast carcinogenesis where BRCA1/2 deficiency augments sensitivity of breast tissue to both estrogen and oxidative stress. ROS activates NF through IKK degradation. NF is required for normal lobulo-alveolar development of mammary gland. The over-expression or aberrant NF subunits eventually results in the enhanced expression of NF responsive genes like cyclin E that contributes to breast cancer progression, cyclin E is expressed in many breast cancer cell lines and associated with poor prognosis. NF regulates breast cancer metastasis, through up-regulating genes including NOS, COX-2 and VEGF. We have noticed a tremendous expression of NF in breast tumor as compared to the surrounding which supports that NF is one important factor that is associated with breast cancer progression. Modifications in the cellular thiol redox state, due to Nrf2 induction of antioxidants expression, may affect the phosphorylation of critical residues of NF that contribute to its nuclear import. This has recently been explained in human breast cancer and earlier demonstrated in other, like bladder cancers that zinc finger E-box binding homeobox 1 (ZEB1) is associated with the development of epithelial to mesenchymal transition (EMT). The EMT has been shown to be the stepping stone in different types of cancers including breast cancer. A transcription regulator ZEB1 targets E-cadherin repression which is a prerequisite for EMT state. So, it is noteworthy that the EMT status linked to ZEB1 expression does not only indicate the mechanistic steps of disease pathogenesis but also it could be a potential therapeutic target. The strategy of the therapeutic approach in breast cancer depends on the stages of the disease. Recent approaches includes from combined chemotherapeutic to radio-therapeutic measures. Doxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. Recent study shows that the efficacy of DOX is significantly increased by cholesterol depleting agent methyl–cyclodextrin (MCD) with an involvement of p53. The p53 activation has been shown to be mediated by the induction of FasR/FasL (Fas Receptor Ligand) pathway. Breast cancers with positive expression of Estrogen Receptor (ER+) are treated with anti-hormone/endocrine therapy which targets the activity of the receptor. Ability of genomics in unraveling rare mutations and gene rearrangements that may impact the development of resistance and therefore treatment of ER+ breast cancer. In the current study it is clearly demonstrated that intracellular redox state may influence the E2 metabolizing enzyme like SULT1E1 expressions and the functions of several antioxidant enzymes. Moreover redox-regulated Nrf-2 and NF has a strong correlation with SULT1E1 expression and the disease severity.

• #1 Pathophysiology | Breast Cancer Case Study

  https://u.osu.edu/breastcancercasestudy2019/pathophysiology-description/

  Except for skin cancer, breast cancer is the most common cancer in American women. Most breast cancer occurs in women older than 50 years. The major risk factors for breast cancer are classified as reproductive, such as nulliparity and pregnancy-associated breast cancer; familial, such as inherited gene syndromes; and environmental and lifestyle, such as hormonal factors and radiation exposure. Some examples of known carcinogenic agents with sufficient evidence in humans that contribute to the development of breast cancer are alcoholic beverages, diethylstilbestrol, estrogen-progestogen contraceptives, estrogen-progestogen menopausal therapy, X-radiation and -radiation. […] Overall, lifetime risk of breast cancer is reduced in parous women compared to nulliparous women, but pregnancy must occur at a young age. The influence of pregnancy on the risk of cancer also depends on family history, lactation postpartum, and overall parity. Breast gland involution after pregnancy and lactation uses some of the same tissue remodeling pathways activated during wound healing. The presence of macrophages in the involuting mammary gland contributes to carcinogenesis.

• #1 Breast cancer: Symptoms, causes, stages, types, and more

  https://www.medicalnewstoday.com/articles/316492

  Females who inherit certain mutations in the BRCA1 and BRCA2 genes have a higher chance of developing breast cancer, ovarian cancer, or both. Mutations in the TP53 gene also have links to an increased breast cancer risk. […] A person with a previous history of breast cancer is more likely to develop the condition than a person who has not had it before. Having some types of noncancerous breast conditions, including atypical ductal hyperplasia or lobular carcinoma in situ, also increases the risk of developing breast cancer. […] Extended exposure to estrogen and progesterone may increase the risk of breast cancer. This exposure could involve starting periods early or entering menopause late. […] Some research associates hormone replacement therapy (HRT), specifically estrogen-progesterone therapy, with an increased risk of breast cancer. […] A survival rate describes how long a person with breast cancer is likely to live after diagnosis compared with someone who does not have the condition. […] The NCI currently estimates that about 91% of females with breast cancer will survive for at least five years after diagnosis.

• #1 Pathogenesis, prevention, diagnosis and treatment of breast cancer

  https://www.wjgnet.com/2218-4333/full/v5/i3/283.htm

  Breast cancer is the most common cancer and also the leading cause of cancer mortality in women worldwide. Approximately 1.38 million new breast cancer cases were diagnosed in 2008 with almost half of all breast cancer cases and nearly 60% of deaths occurring in lower income countries. There is a large variation in breast cancer survival rates around the world, with an estimated 5-year survival of 80% in high income countries to below 40% for low income countries. […] Age, reproductive factors, personal or family history of breast disease, genetic pre-disposition and environmental factors have been associated with an increased risk for the development of female breast cancer. The risk of developing breast cancer increases with age. A personal history of breast cancer is also a significant risk factor for the development of a second ipsilateral or contralateral breast cancer. Proliferative breast disease is associated with an increased risk of breast cancer. Atypical hyperplasia including both ductal and lobular, usually incidentally found on screening mammography, confers a substantial increased risk of breast cancer. A woman’s risk of breast cancer is increased if she has a family history of the disease. Approximately 20%-25% of breast cancer patients have a positive family history but only 5%-10% of breast cancer cases demonstrate an autosomal dominant inheritance. High-risk predisposition alleles conferring a 40%-85% lifetime risk of developing breast cancer include BRCA1 and BRCA2 mutations.

• #1 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://www.mdpi.com/2072-6694/14/10/2569

  Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. […] The unambiguous cause of carcinogenesis has not yet been established, but several risk factors conducive to the development of breast cancer are known. One of the most important, as also indicated by the epidemiological data described above, are the gender, age, and degree of economic development of a given country. […] Factors related to a woman’s hormonal status seem to have a huge impact on the risk of developing breast cancer. The results of many studies indicate that the risk of developing breast cancer increases in proportion to the time of exposure to estrogen, which prolongs early menarche, late menopause, the age of birth of the first child and the number of children born.

• #1 Pathogenesis, prevention, diagnosis and treatment of breast cancer

  https://www.wjgnet.com/2218-4333/full/v5/i3/283.htm

  The cycles of endogenous estrogen levels throughout a woman’s lifetime have implications for the development of or the protection against breast cancer. Early age at menarche is a risk factor among both pre- and postmenopausal women for developing breast cancer. Nulliparous women are at an increased risk for the development of breast cancer compared to parous women. Evidence suggests that breastfeeding has a protective effect against the development of breast cancer. High endogenous sex hormone levels increase the risk of breast cancer in both premenopausal and postmenopausal women. Later onset of menopause has also been associated with increased breast cancer risk. […] Evidence suggests a relationship between the use of hormone replacement therapy (HRT) and breast cancer risk. Breast cancers related to HRT use are usually hormone receptor positive. Timing and duration of HRT seem to be important factors associated with breast cancer risk as well. Modifiable risk factors including the excessive use of alcohol, obesity and physical inactivity account for 21% of all breast cancer deaths worldwide. Alcohol consumption has been associated with increased breast cancer risk that is statistically significant at levels as low as 5.0 to 9.9 g per day. Obesity, specifically in postmenopausal women, has also been shown to increase a woman’s risk of breast cancer.

• #1 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9139759/

  Numerous studies indicate a relationship between alcohol consumption and an increased risk of breast cancer. […] One of the risk factors for developing breast cancer, confirmed in many studies, is obesity. […] Obesity is a recognized risk factor for breast cancer and the development of relapses, even if patients are properly treated. […] Ionizing radiation (IR) increases the risk of breast cancer, especially in women and when exposed at a younger age, and the evidence generally supports the linear dose-response relationship. […] The influence of the type of diet used on the development of the cancer process has been the subject of numerous studies. […] The assessment of the achievements over recent years in the treatment of patients with breast cancer, with the simultaneous lack of fully satisfactory results and satisfactory solutions, suggests that further progress in the development of new methods of combating cancer will bring us closer to a new era in this field.

• #1 Breast Cancer – Gynecology and Obstetrics – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/gynecology-and-obstetrics/breast-cancer/breast-cancer

  Breast cancer invades locally and spreads through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the bodymost commonly, lungs, liver, bone, brain, and skin. […] Estrogen and progesterone receptors are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. Thus, medications that block these receptors are useful in treating and preventing tumors with the receptors. […] For tumors in which HER2 receptors are overexpressed, medications that block these receptors are part of standard treatment. HER2 overexpressing tumors respond well to these medications because HER2 is a significant driver of cancer cell progression. […] BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer to 70%. Prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% and should be offered to women with a BRCA mutation. Other genetic mutations that increase the risk of developing breast cancer include mutations in CHEK2, PALB2, ATM, RAD51C, RAD51D, BARD1, and TP53, which are usually included in panel genetic testing.

• #1 Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds | Anticancer Research

  https://ar.iiarjournals.org/content/38/5/2607

  Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. […] Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. […] Metastatic breast cancer originates within the breast and disseminates from its primary site to nearby lymph nodes as well as other more distant sites throughout the body. […] After metastasis, breast cancer cells are found to be less responsive to chemotherapy. […] In women, breast cancer is the most common cause of cancer death, and approximately 90% of breast cancer deaths are associated with metastasis of cancer cells. […] The development of breast cancer is associated with several risk factors such as age, hormone status, family history and genetic predisposition.

• #1 Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds | Anticancer Research

  https://ar.iiarjournals.org/content/38/5/2607

  Generally, breast cancer cell dissemination comprises the common metastasis process found in many solid tumors. […] Metastasis starts with the disruption of the connection of the cell to ECM via cellular adhesion proteins such as integrins, leading to cancer cell dissociation from adjacent cells and the basement membrane. […] The EMT process starts with losing expression of epithelial markers such as E-cadherin, occludin and cytokeratin. […] Importantly, a decrease of E-cadherin expression is a key indicator of epithelial-to-mesenchymal transition (EMT), a cellular process that plays a critical role in cancer progression and metastasis. […] TGF has been shown to function as an EMT inducer. […] The PI3K/AKT/mTOR pathway is often up-regulated in breast cancer. […] The anti-angiogenesis therapeutic approach has gained much attention in the anti-cancer drug discovery area.

• #1 Epidemiology, risk factors and mechanism of breast cancer and atrial fibrillation | Cardio-Oncology | Full Text

  https://cardiooncologyjournal.biomedcentral.com/articles/10.1186/s40959-024-00298-y

  ROS induce DNA mutations and activate the PI3K/AKT/NF-B signaling pathway, triggering the expression of metastasis-associated genes and mediating the epithelial-to-mesenchymal transition (EMT) process in breast cancer stem cells. […] The PI3K/AKT and MAPK signaling pathways may play crucial roles in the pathogenesis of both breast cancer and AF. […] In breast cancer, the MAPK signaling pathway significantly enhances tumor cell migration and invasion by activating a series of downstream molecules. […] These actions contribute to myocardial hypertrophy, fibrosis, and accelerate atrial electrophysiological remodeling and structural changes. […] The renin-angiotensin-aldosterone system(RAAS) triggers oxidative stress, the production of ROS, and the release of cytokines, which are common mechanisms underlying the development of both breast cancer and AF.

• #1 Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds | Anticancer Research

  https://ar.iiarjournals.org/content/38/5/2607

  Several angiogenesis-potentiating factors have been identified and among them the expression of certain endothelial growth factors such as vascular endothelial growth factor (VEGF) shows the most potent activity, enhancing angiogenesis in various cancer types. […] Despite the high rate of cancer-related death in patients with metastatic breast cancer, therapeutic approaches in preventing metastasis are currently restricted. […] Oleuropein, a major bioactive polyphenol of Olea europaea, the olive tree, exhibited strong anti-invasive effects when tested on breast cancer cells. […] Matrine, a major bioactive compound isolated from Sophora flavescens Ait, was investigated for potential pharmacological activities. […] Curcumin has several anticancer properties such as anti-metastasis, anoikis sensitization, chemotherapeutic drug sensitization, and direct apoptosis induction in various types of cancer.

• #1 Researchers unlock mechanism of drug resistance in aggressive breast cancer – UNC Lineberger

  https://unclineberger.org/news-archives/researchers-unlock-mechanism/

  Breast cancer cells are evasive, finding ways to bypass drugs designed to stop their unchecked growth. […] In a new study, researchers uncovered a mechanism of resistance used by a particularly aggressive breast cancer type, and revealed a possible drug combination that could stop cancer growth and also help to prevent resistance. […] What we found is that tumor resistance to this type of drug involves what we call adaptive reprogramming of the genome. […] However, cancer cells can change the expression of genes in alternative protein pathways in order to skirt around the blocked pathway, allowing them to restart uncontrolled cell growth. […] In particular, triple negative breast cancer cells treated with trametinib altered their genetic landscape by forming several thousand new enhancers DNA sequences that help to turn on specific genes.

• #1 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://www.mdpi.com/2072-6694/14/10/2569

  The expression of steroid receptors—estrogenic and progesterone—is particularly important due to the favorable value of both prognostic and predictive value for hormonal treatment. […] The prognostic and predictive value for targeted treatment is also the overexpression of the HER-2 receptor or amplification of the HER-2 gene. […] The Ki67 protein, used in the evaluation of the cellular proliferation index, is a nuclear protein present in all phases of cell division, except the resting phase of G0, and therefore in all actively proliferating cells. […] The development of molecular biology and genetics allowed for the separation of many new prognostic factors (mainly genes), and the introduction of new technologies to create tools for their determination. […] The assessment of the achievements over recent years in the treatment of patients with breast cancer, with the simultaneous lack of fully satisfactory results and satisfactory solutions, suggests that further progress in the development of new methods of combating cancer will bring us closer to a new era in this field.

• #1 Breast Cancer – Gynecology and Obstetrics – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/gynecology-and-obstetrics/breast-cancer/breast-cancer

  Most breast cancers are epithelial tumors (carcinomas) that develop from cells lining ducts or lobules; nonepithelial cancers of the supporting stroma (eg, angiosarcoma, primary stromal sarcomas, phyllodes tumor) are less common. […] Epithelial cancers may express hormone receptors (stromal tumors do not express hormone receptors, eg, phyllodes tumors). Approximately 80% of postmenopausal and 20% of premenopausal patients with breast cancer have an estrogen receptor-positive (ER+) tumor; approximately 70% of all breast cancers are progesterone receptor-positive. Another cellular receptor is human epidermal growth factor receptor 2 (HER2; also called HER2/neu or ErbB2); its presence correlates with a poorer prognosis at any given stage of cancer. In approximately 15% of patients with breast cancer, HER2 receptors are overexpressed.

• #1 Breast Cancer Pathophysiology | Oncology Nurses Quality Improvement Series

  https://oncologynurse-ce.com/breast-cancer-pathophysiology/

  HER2 is a gene that produces HER2 (HER2/neu) proteins, which help control how healthy breast cells grow, divide, and repair. However, HER2 can be associated with aggressive types of breast cancer if the HER2 gene is amplified (too many protein copies made) and the protein overexpressed (too many HER2 receptors created). […] Hormone and HER2 receptor factors have value in determining disease stage, recurrence estimation, and prognostic therapeutic response. The four main subtypes of breast cancer include: Subtype HR+/HER2 – is the most prevalent (67%), more than six times higher than triple negative cancers. HER2-positive subtypes are much less common, with 2012-2016 data revealing a total of 14% of cases for both Luminal B and HER2-enriched subtypes combined. […] Clinical and pathological characteristics of tumors can potentially influence therapy choice and even expected outcomes, or prognosis. Tissues can be evaluated for such features through conventional histology, immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), molecular and genetic profiling. For example, certain histologic types can have prognostic importance, such as medullary carcinoma and variants of invasive ductal carcinomas (adenoid cystic and tubular carcinomas), which can have favorable natural histories. Alternatively, triple-negative subtyping tends to have the worst survival of all four breast cancer classifications. Above all, stage at diagnosis (localized, regional or distant) may have the greatest impact in determining long-term survival. […] Of particular importance in prognosis determination and therapeutic response prediction to endocrine and HER2-directed therapies are ER, PR, and HER2 status.

• #1 Epidemiology, risk factors and mechanism of breast cancer and atrial fibrillation | Cardio-Oncology | Full Text

  https://cardiooncologyjournal.biomedcentral.com/articles/10.1186/s40959-024-00298-y

  Activation of the RAAS system increases the risk of AF by promoting inflammatory responses, inducing cardiac electrical remodeling, and enhancing the accumulation of epicardial fat tissue. […] The mechanisms of cardiotoxicity induced by antibody-drug conjugates such as T-DM1 and T-DXd include all the mechanisms associated with trastuzumab. […] The mechanisms by which endocrine therapy promotes the development of AF may be related to the reduced cardioprotective effects associated with low estrogen levels induced by endocrine therapy.

• #1 The Role of Interleukin-8 and Its Mechanism in Patients with Breast Cancer: Its Relation with Oxidative Stress and Estrogen Receptor

  https://brieflands.com/articles/ijcm-8791.html

  Oxidative stress drives the initiation and progression of cancer via mutations caused by DNA damage and plays the angiogenesis and metastasis of breast cancer. Therefore, oxidative stress caused angiogenic factor production, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) via cancer cells. Hence, oxidative stress significantly motivated the migratory potential of poorly invasive breast cancer cells MCF-7 via Erk signaling activation, resulted in pro-migratory chemokine IL-8 secretion.

• #1 Unifying mechanism in the initiation of breast cancer by metabolism of estrogen (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6738

  Excessive ROS serves as an important effector to increase genomic instability and activate the redox-associated signaling pathway. […] Estrogen-mediated high ROS accumulation serves a key role in driving carcinogenesis. […] The regulation of metabolism enzymes, which are responsible for estrogen metabolism, are critical for the homeostasis of estrogen.

• #1 Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds | Anticancer Research

  https://ar.iiarjournals.org/content/38/5/2607

  Sinomenine was shown to have various pharmacological effects such as anti-inflammatory, anti-arthritis, and anticancer. […] A natural compound from Atractylodes lancea named codonolactone was shown to attenuate the metastatic ability of breast cancer both in vitro and in vivo. […] Grape polyphenols, such as resveratrol, quercetin and catechin, were shown to inhibit growth of breast cancer and metastasis in nude mice with mechanisms involving suppression of AKT and mTOR activities. […] Understanding all of the key signals regulating breast cancer metastasis and the information of potential compounds affecting such pathways is beneficial for the development of drugs and strategies to inhibit cancer spread with greater efficiency, and improve the clinical outcome of patients with breast cancer.

• #2 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://www.mdpi.com/2072-6694/14/10/2569

  Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. […] The unambiguous cause of carcinogenesis has not yet been established, but several risk factors conducive to the development of breast cancer are known. One of the most important, as also indicated by the epidemiological data described above, are the gender, age, and degree of economic development of a given country. […] Factors related to a woman’s hormonal status seem to have a huge impact on the risk of developing breast cancer. The results of many studies indicate that the risk of developing breast cancer increases in proportion to the time of exposure to estrogen, which prolongs early menarche, late menopause, the age of birth of the first child and the number of children born.

• #2 Breast cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/breast-cancer/symptoms-causes/syc-20352470

  Breast cancer is a kind of cancer that begins as a growth of cells in the breast tissue. […] Healthcare professionals know that breast cancer starts when something changes the DNA inside cells in the breast tissue. A cell’s DNA holds the instructions that tell a cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells. […] The DNA changes that lead to breast cancer most often happen in the cells that line the milk ducts. These ducts are tubes designed to carry milk to the nipple. Breast cancer that starts in the ducts is called invasive ductal carcinoma. Breast cancer also can start in cells in the milk glands. These glands, called lobules, are designed to make breast milk. Cancer that happens in the lobules is called invasive lobular carcinoma. Other cells in the breast can become cancer cells, though this isn’t common.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Breast-Cancer-Pathophysiology.aspx

  Breast cancer is a malignant tumor that starts in the cells of the breast. Like other cancers, there are several factors that can raise the risk of getting breast cancer. Damage to the DNA and genetic mutations can lead to breast cancer have been experimentally linked to estrogen exposure. Some individuals inherit defects in the DNA and genes like the BRCA1, BRCA2 and P53 among others. Those with a family history of ovarian or breast cancer thus are at an increased risk of breast cancer. […] The immune system normally seeks out cancer cells and cells with damaged DNA and destroys them. Breast cancer may be a result of failure of such an effective immune defence and surveillance. […] These are several signalling systems of growth factors and other mediators that interact between stromal cells and epithelial cells. Disrupting these may lead to breast cancer as well.

• #2 Breast cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Breast_cancer_pathophysiology

  Genes involved in the pathogenesis of breast cancer include BRCA1, BRCA2 and p53. On microscopic histopathological analysis, minimal tubule formation, marked pleomorphism, and numerous mitotic figures are characteristic findings of breast cancer. […] Majority of breast malignancies arise from epithelial cells and hence are carcinomas. Microscopic appearance and biologic behavior divide breast carcinomas to several diverse groups. Based upon the growth pattern and cytologic features of the lesions, the in situ carcinomas of the breast divide into ductal (also known as intraductal carcinoma) or lobular. […] Ductal carcinoma in situ (DCIS) is described as a proliferation of abnormal cells confined within the mammary ductal system. DCIS signifies a herald to invasive breast cancer. […] Breast cancer, like other cancers, occurs because of an interaction between the environment and a defective gene. Normal cells become cancerous when mutations destroy their ability to stop dividing, to attach to other cells, and to stay where they belong.

• #2 Breast Cancer Pathophysiology | Oncology Nurses Quality Improvement Series

  https://oncologynurse-ce.com/breast-cancer-pathophysiology/

  The most common cause of hereditary breast cancer is a BRCA1 or BRCA2 genetic mutation inheritance, conferring a 7 in 10 chance of developing breast cancer by the age of 80. Women with either of these mutations are also more likely to be diagnosed with this cancer not only at a younger age, but also cancer in bilateral breasts, as well as ovarian cancer. Other genetic mutations are far less common, and generally do not increase risk of breast cancer development as significantly as BRCA mutations. […] Breast cancer classification is categorized into four main subtypes focusing on pathological assessment of hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor 2 (HER2) status. Each has their own role in tumor development and can be targeted for anti-tumoral directed therapy. Estrogen and progesterone can promote growth of tumors that express receptors for these hormones. Hormone receptor-positive breast cancers are particularly prominent, with approximately two of every three cancers testing positive for hormone receptors.

• #2 Breast cancer – McMaster Pathophysiology Review

  https://www.pathophys.org/breast-cancer/

  Breast cancer requires a hormonal supply to develop, much like the tissue it arises out of. Risk of breast cancer increases with lifetime estrogen exposure. The majority of breast cancers are hormone sensitive, meaning that they express estrogen receptors and proliferate in response to estrogen stimulation. Endocrine therapies that inhibit estrogen production are effective in treating hormone-sensitive breast cancer. […] Two different types of estrogen receptors exist, alpha and beta (ER and ER respectively). Various tissues express these receptors with breast, ovaries and the endometrium expressing ER, while the kidneys, brain, lungs and several other organs expressing ER. The role of ER in carcinogenesis remains controversial whereas, a clear contribution of ER protein has been established.

• #2 Unifying mechanism in the initiation of breast cancer by metabolism of estrogen (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6738

  The greater carcinogenic activity of 4-OHE1(E2) is associated with a higher amount of depurinating DNA adducts formed by E1(E2)-3,4-Q, compared with E1(E2)-2,3-Q. […] Accumulating evidence for the initiation of cancer by estrogen-DNA adducts has been identified by using human breast epithelial cell lines such as MCF-10F, which is an immortalized, non-transformed ER-a-negative cell line. […] The results further indicate that transformation occurs via the genotoxic effects of the estrogen metabolites. […] The mutagenicity of E1(E2)-3,4-Q was first studied in female SENCAR mice by determining the H-ras mutations induced, and the estrogen-DNA adducts formed. […] High levels of estrogen-DNA adducts have been seen in analyses of urine and serum from women that are at high risk of breast cancer.

• #2 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9139759/

  Estrogens play an important role in the pathogenesis of the development of breast cancer. Breast cancer is considered a hormone-dependent tumor in which elevated estrogen levels and longer exposure to this hormone are associated with an increased risk of its development. […] The presence of mutations in these genes occurs only in 35% of breast cancer patients. However, due to the high penetration of BRCA1/BRCA2 genes, these patients should be included in the prophylactic program. Carriers of the BRCA1/BRCA2 mutation are estimated to have a 10-fold higher risk of developing breast cancer. […] The use of HRT is a significant risk factor for breast cancer. […] The relationship between hormonal contraceptive use and breast cancer risk has been demonstrated in two important papers. […] A recognized factor in the development of breast cancer is early exposure to ionizing radiation.

• #2 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9139759/

  The unambiguous cause of carcinogenesis has not yet been established, but several risk factors conducive to the development of breast cancer are known. One of the most important, as also indicated by the epidemiological data described above, are the gender, age, and degree of economic development of a given country. No less important are hormonal factors, mainly related to the time of exposure to estrogens, procreative factors, including the number of children born, the age of birth of the first child, or breastfeeding. Great importance in the development of breast cancer is attributed to genetic factors, the use of hormone replacement therapy, improper diet, and the resulting obesity. […] Factors related to a woman’s hormonal status seem to have a huge impact on the risk of developing breast cancer. The results of many studies indicate that the risk of developing breast cancer increases in proportion to the time of exposure to estrogen, which prolongs early menarche, late menopause, the age of birth of the first child and the number of children born.

• #2 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://www.mdpi.com/2072-6694/14/10/2569

  A recognized factor in the development of breast cancer is early exposure to ionizing radiation. […] Ionizing radiation (IR) increases the risk of breast cancer, especially in women and when exposed at a younger age, and the evidence generally supports the linear dose-response relationship. […] The influence of the type of diet used on the development of the cancer process has been the subject of numerous studies. […] One of the risk factors for developing breast cancer, confirmed in many studies, is obesity. […] Research reports on the impact of chronic nicotinism on the increased risk of breast cancer are contradictory. […] The basis for the diagnosis of breast cancer remains standard pathomorphological diagnostics. […] The current VIII edition of the TNM classification was published by the AJCC (American Joint Committee on Cancer) in 2018.

• #2 Researchers unlock mechanism of drug resistance in aggressive breast cancer – UNC Lineberger

  https://unclineberger.org/news-archives/researchers-unlock-mechanism/

  We really saw vast remodeling of the genomic landscape in response to therapy. […] They found that pairing the investigational anti-BRD4 drug with trametinib helped to stop tumor growth in experiments in cells and in mouse models. […] In fact, we were able to reverse the development of resistance to trametinib. […] Johnson and his colleagues found that their prediction of resistance to these drugs from laboratory models held true in the human breast cancers, lending further support to approaches they are developing to prevent this resistance. […] Drug resistance is a major problem in triple negative breast cancer, and is the reason so many promising drugs for this challenging kind of breast cancer have failed.

• #2 Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9139759/

  Numerous studies indicate a relationship between alcohol consumption and an increased risk of breast cancer. […] One of the risk factors for developing breast cancer, confirmed in many studies, is obesity. […] Obesity is a recognized risk factor for breast cancer and the development of relapses, even if patients are properly treated. […] Ionizing radiation (IR) increases the risk of breast cancer, especially in women and when exposed at a younger age, and the evidence generally supports the linear dose-response relationship. […] The influence of the type of diet used on the development of the cancer process has been the subject of numerous studies. […] The assessment of the achievements over recent years in the treatment of patients with breast cancer, with the simultaneous lack of fully satisfactory results and satisfactory solutions, suggests that further progress in the development of new methods of combating cancer will bring us closer to a new era in this field.

• #3 Pathogenesis, prevention, diagnosis and treatment of breast cancer

  https://www.wjgnet.com/2218-4333/full/v5/i3/283.htm

  Breast cancer is the most common cancer and also the leading cause of cancer mortality in women worldwide. Approximately 1.38 million new breast cancer cases were diagnosed in 2008 with almost half of all breast cancer cases and nearly 60% of deaths occurring in lower income countries. There is a large variation in breast cancer survival rates around the world, with an estimated 5-year survival of 80% in high income countries to below 40% for low income countries. […] Age, reproductive factors, personal or family history of breast disease, genetic pre-disposition and environmental factors have been associated with an increased risk for the development of female breast cancer. The risk of developing breast cancer increases with age. A personal history of breast cancer is also a significant risk factor for the development of a second ipsilateral or contralateral breast cancer. Proliferative breast disease is associated with an increased risk of breast cancer. Atypical hyperplasia including both ductal and lobular, usually incidentally found on screening mammography, confers a substantial increased risk of breast cancer. A woman’s risk of breast cancer is increased if she has a family history of the disease. Approximately 20%-25% of breast cancer patients have a positive family history but only 5%-10% of breast cancer cases demonstrate an autosomal dominant inheritance. High-risk predisposition alleles conferring a 40%-85% lifetime risk of developing breast cancer include BRCA1 and BRCA2 mutations.

• #3 Breast Cancer Pathophysiology | Oncology Nurses Quality Improvement Series

  https://oncologynurse-ce.com/breast-cancer-pathophysiology/

  HER2 is a gene that produces HER2 (HER2/neu) proteins, which help control how healthy breast cells grow, divide, and repair. However, HER2 can be associated with aggressive types of breast cancer if the HER2 gene is amplified (too many protein copies made) and the protein overexpressed (too many HER2 receptors created). […] Hormone and HER2 receptor factors have value in determining disease stage, recurrence estimation, and prognostic therapeutic response. The four main subtypes of breast cancer include: Subtype HR+/HER2 – is the most prevalent (67%), more than six times higher than triple negative cancers. HER2-positive subtypes are much less common, with 2012-2016 data revealing a total of 14% of cases for both Luminal B and HER2-enriched subtypes combined. […] Clinical and pathological characteristics of tumors can potentially influence therapy choice and even expected outcomes, or prognosis. Tissues can be evaluated for such features through conventional histology, immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), molecular and genetic profiling. For example, certain histologic types can have prognostic importance, such as medullary carcinoma and variants of invasive ductal carcinomas (adenoid cystic and tubular carcinomas), which can have favorable natural histories. Alternatively, triple-negative subtyping tends to have the worst survival of all four breast cancer classifications. Above all, stage at diagnosis (localized, regional or distant) may have the greatest impact in determining long-term survival. […] Of particular importance in prognosis determination and therapeutic response prediction to endocrine and HER2-directed therapies are ER, PR, and HER2 status.

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