br Introduction Breast cancer is the most
Introduction Breast cancer is the most common cancer in women and one of the leading causes of death worldwide. Estrogen receptor alpha (ERα, “wild-type” estrogen receptor), encoded by the estrogen receptor1 (ESR1) gene, is expressed in approximately 70% of all breast cancers. Hormonal therapy has become the mainstay in treatment of ER+ breast cancer and prevention of disease recurrence , . The most commonly used anti-estrogen therapies inhibit ER activity by either targeting the ER protein itself or depriving the receptor of its ligand. The different DAMGO of endocrine treatments include (1) direct inhibition of ER by selective estrogen modulators (SERMs) with mixed agonistic/antagonistic activities, such as Tamoxifen (TAM), (2) selective ER degraders (SERDs) such as Fulvestrant that are more potent anti-estrogens, and treatment strategies that deplete systemic estrogen levels by either (3) aromatase inhibitors or (4) ovarian suppression , . While endocrine therapies have proven to be very effective in both the early and the metastatic settings; both de novo and acquired resistance to endocrine treatments remain a key clinical challenge , , . TAM is the first endocrine therapy in clinical use against breast cancer . TAM binds to the receptor and can exhibit both agonist and antagonist properties, with agonistic effects on endometrium and antagonist effects on mammary tissue. Thus, the selectivity of responses led to it being described as a selective estrogen receptor modulator (SREM). TAM is considered as first line hormonal therapy in premenopausal women with ER+ breast cancer. Other anti-estrogens affect the stability of the ER and down regulate the receptor protein; these drugs often referred as pure anti-estrogens . Currently, Fulvestrant is the most widely studied of this anti-estrogen class; which act by inhibition of ER protein dimerization leading to degradation of the receptor protein . Given the mechanism of action of these drugs, they are described as a selective estrogen receptor downregulator/degraders (SERDs). Another category of anti-estrogens are Aromatase Inhibitors (AIs), which act to decrease circulating estrogen levels by interfering with estrogen production in the peripheral tissues. They are now considered as standard first line hormone therapy in postmenopausal women with ER+ breast cancer . Other classes of drugs (CDK4/6 inhibitors, PI3K inhibitors, new ER antagonists) are being developed for adjuvant endocrine therapy in second or third regimens in patients with recurrent breast cancer, some of which were administered to the subjects in our study population. Estrogens are synthesized from puberty until menopause within the ovaries. After menopause, ovarian estrogen ceases but other tissues in the body including the brain, adipose tissue and muscles continue to produce estrogens from androgens by the action of the aromatase enzyme (CYP 19) . Normal ERα, a nuclear protein, is ligand dependent. Estrogen-ER complex will activate the receptor and induce conformational changes, allowing the complex to bind to particular DNA sequences. Meanwhile, co-repressors and co-activators could influence the process of gene transcription . Therefore, anti-estrogens act primarily to block ER or deplete endogenous estrogen preventing ER activation and tumor growth.