Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMP second messenger.  Hence the SHBG/SHBG-R complex appears to act as a transmembrane steroid receptor that is capable of transmitting signals to the interior of cells.
Mitogenic function of E-ER relies on the presence of sufficient supply of nutrients such as glucose, because E-ER signaling also promotes the glycolysis and Krebs cycling [ 75 ]. A recent work, however, reported that estrogen up-regulates glycolysis via activation of PI3K-AKT signaling pathway, promotes cell proliferation under high glucose condition and represses Krebs cycle simultaneously [ 76 , 77 ]. This is similar to the situation in proliferating cancer cells that consume glucose and rely on glycolysis over Krebs cycle in generating ATP, which is termed as “Warburg effect” [ 78 ]. However, when the extracellular glucose decreases, estrogen treatment activates mitochondria respiration via up-regulating PDH (pyruvate dehydrogenase) activity and repressing glycolysis [ 76 ], suggesting estrogen's effect on cell metabolism is adaptable and is under control of glucose availability. In the scenarios of cancer prone condition, glucose is frequently enriched. Estrogen probably promotes the cell proliferation by stimulating the anabolic metabolism. In fact, release of glycolysis proteins into plasma precedes the diagnosis of ER + breast carcinoma [ 79 ], suggesting E-ER signaling promoted glycolysis is a very early event that associates with tumorigenesis. It was shown that the genes maximally induced by estrogen treatment after relatively long time (160 mins) incubation have the top hit of GO (gene ontology) term “cellular biosynthetic process” by ontology analysis [ 67 ]. These observations indicate E-ER signaling plays an important role in promoting tumor growth. But the E-ER signaling may also have its own risk management strategy because BRCA1 is responsive to E-ER signaling, and the response of BRCA1 needs to be mediated by CtBP and the cell metabolite NADH [ 65 ]. Estrogen was found to be able to activate tumor suppressor gene expression via manipulation of the cellular metabolism status globally [ 65 ]. Although BRCA1 function in regulating cell metabolism pathways has just been realized, several recent findings suggested that BRCA1 is a negative regulator of anabolic cell metabolism. BRCA1 has been shown to negatively regulate Igf-1 expression and mediate phosphorylated AKT degradation [ 80 , 81 ]. Also, BRCA1 directly inhibits ACC (acetyl-CoA carboxylase) by interacting with it [ 82 ]. ACC catalyzes the converting of Acetyl-CoA to malonyl-CoA during fatty acid synthesis which is essential for tumor cell growth [ 83 ]. Since de novo fatty acid synthesis frequently associates with cancer cell growth, and probably the EMT, it suggests BRCA1 has novel tumor repressor function by controlling fatty acids metabolism. Thus, E-ER activated BRCA1 expression forms an important negative regulatory feedback that slows down the anabolic process promoted by E-ER.
2008 – 2017 Adaptogeny .
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