Cancer
Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:- First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.
- Second, estrogen metabolism produces genotoxic waste.
Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.[25] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[26] Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.
Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.[27]
Phytoestrogens such as quercetin can modulate estrogen receptor’s activities in such a way that it may prevent cancers including breasts, prostate, and colon all by promoting apoptosis.[28] Quercetin selectively binds to the estrogen receptor beta (ERβ).[29] This was tested in HeLa cells which were treated with a pure estrogen receptor antagonist which blocked both estradiol and quercetin from inducing the caspase-3 activation.[28] ERβ is expressed in the human colon and activates a specific signal transduction pathway that controls apoptosis in the colon and works by being activated by estradiol and more recently found to possibly be activated by quercetin.[28] Quercetin activates the ERβ along with the apoptotic cascade when caspase-3 is present by the phosphorylation of p38 kinase. In colon cancers and tumors ERβ and its pathway have been proven to be significantly decreased thus allowing the tumors to thrive.[30]
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This pathogenesis does not however explain the triple Negative scenario where receptor are supposedly "inexistant" and are not stimulated by Estrogen. Failure of the receptor leads to secondary stimulation of "unplanned receptor"
the man pathways are not the same, the stress MAPK , c-JUN is the one over expressed in our proposed model, The failure is a deficiency in the Heparan sulfate component. In most case the defect is congenital. It take years of stimulation for normal gene to take a neoplastic shift, that time can be 20-40 years. That's why these condition are seen in the young. (ie in polycystic kidney diseases it take 30-40 years to start developing kidney failure and a full blown terminal syndrome killing the individual in the 50s and rarely early 60s).
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