Estrogen enhances the risk of developing breast cancer. Non-genomic effects of estrogen result from signal transduction originating at the membrane, in part from cross talk between ER and the EGF receptor. Cell based systems will establish that blocking E2-signaling through ERK and Pl3 kinase for 3 days substantially prevents the proliferation of cultured MCF-7 and ZR-75-1 (ER+) cells. G1 cell cycle targets and GI/S progression are ERK and Pl3K entrained. It is proposed that E2 interacts with BRCA1 to promote breast cancer. The ability of E2 to activate ERK will be shown to be down regulated by expression of wild type but not mutant BRCA1 in HCC-1937 cells (express a mutant BRCA1), co-transfected to express ER. This model will also determine whether wtBRCA1 can block the proliferative and ERK-inducing effects of E2, in cells cultured for 3 days. We will implicate the membrane receptor by expressing a dominant negative ER that only abrogates endogenous membrane ER function, and by targeting the E domain to the membrane. It is proposed that E2 binds the membrane ER, activates discrete G proteins that activate Src. Src activates specific matrix metalloproteinases that liberate HB-EGF and transactivates the EGFR or ErbB2. This leads to ERK and PI3K activation in breast cancer cells. This will be shown using dominant negative constructs SiRNA, and cells deficient for EGFR or ErbB2. We propose that the receptor must also dimerize to signal from the membrane, and we will use expression of a dimer mutant to show this. In-vivo, E domain targeted to membrane or nucleus are stably expressed in ER - breast cancer cells. These cells are injected into nude mice, and growth under estrogen-repleted conditions is determined. The goal is to define non-genomic actions of estrogen that could potentially be antagonized at the membrane, yet preserve the desirable effects of E2 in the nucleus. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Reproductive Endocrinology Study Section (REN)
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Sathyamoorthy, Neeraja
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Southern California Institute for Research/Education
Long Beach
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Levin, Ellis R (2018) Membrane estrogen receptors signal to determine transcription factor function. Steroids 132:1-4
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