Obesity

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. Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer. Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.

Nongenomic

In addition, some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, receptor tyrosine kinases (EGFR and IGF-1), and non-receptor tyrosine kinases (Src). Through striatin, some of this membrane bound ER may lead to increased levels of Ca²⁺ and nitric oxide. Through the receptor tyrosine kinases, signals are sent to the nucleus through the mitogen-activated protein kinase (MAPK/ERK) pathway and phosphoinositide 3-kinase (Pl3K/AKT) pathway. Glycogen synthase kinase-3β inhibits transcription by nuclear ER by inhibiting phosphorylation of serine-118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT and the MAPK/ERK pathways.

G protein-coupled estrogen receptor 1 (GPER) also known as the G protein-coupled receptor 30 (GPR30) is a G protein-coupled receptor that in humans is encoded by the GPER gene. GPR30 is an integral membrane protein with high affinity for estrogen.

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.

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.

Estrogen and the ERs have also been implicated in 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.

Phytoestrogens such as quercetin can modulate ER activities in such a way that it may prevent cancers including breasts, prostate, and colon all by promoting apoptosis. Quercetin activates the ERβ along with the apoptotic cascade involving caspase-3. In colon cancers and other tumors ERβ and its pathway have been proven to be significantly decreased thus allowing the tumors to thrive.

Дата добавления: 2014-01-14