Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E 2 ). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E 2 deprivation (LTED) causes 'adaptive hypersensitivity'. The enhanced responses to E 2 do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E 2 on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERα is 4-to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E 2 binds to cell membrane-associated ERα, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E 2 produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E 2 involved use of cells which selectively expressed ERα in the nucleus, cytosol and cell membrane. We created these COS-1 'designer cells' by transfecting ERα lacking a nuclear localization signal and containing a membrane localizing signal.The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E 2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E 2 . Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.
Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ERα mediates several key side effects of tamoxifen therapy.
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