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• W2791781412 abstract "2934 Breast cancer presents as estrogen receptor alpha (ERα) positive or negative. ERα- tumors have a poor prognosis, are resistant to hormonal therapies, and frequently show overexpression, amplification, and/or hyperactivation of growth factor receptors, such as the erbB family. Using cell line models that mimic this elevated growth factor signaling by EGFR and erbB-2 in MCF-7 breast cancer cells, we have previously shown that hyperactivation of downstream p42/44 MAPK results in the reversible loss of ERα expression, and that in addition to the direct effect of MAPK on ERα, indirect activation of NFkB by MAPK also plays a role. In this study, we set out to determine if the inihibition of MAPK activity in established ERα- breast cancer cell lines could restore ERα expression and further, if this re-expressed ERα could now restore anti-estrogen response. MAPK inhibition via treatment with U0126 in 3 ERα- breast cancer cell lines, the EGFR overexpressing SUM 229s, the EGFR/c-erbB-2 dual overexperssing SUM 190s, and the RhoC overexpressing SUM 149s resulted in the sustained re-expression of ERα protein in all 3 cell lines. To ascertain that this re-expressed ERα could now restore anti-estrogen sensitivity, growth assays analyzing the effects of 4-hydroxy-tamoxifen (4HT) and the pure antiestrogen ICI 182,780 (faslodex) at 10-7 M alone, 5 μM U0126 alone, or the combination of 4HT or ICI and U0126 on cell proliferation were performed by WST-1 assay. ERα- SUM 229 and 149 cells were resistant to both 4HT and ICI. While having no growth inhibitory effects on its own, 5 μM U016 restored the growth inhibitory effects of both 4HT and ICI in ERα- SUM 229 cells, but not in SUM 149 cells. To determine if these in vitro cell line results would extrapolate to a real breast tumor situation, ERα- tumor specimens were obtained from the Tissue Procurement Core. Tumors were minced and divided evenly into a baseline sample and into tissue culture dishes containing medium alone, or supplemented with 10 μM U0126 or vehicle control DMSO. The minced tumor specimens in medium plus or minus U0126 were incubated at 37oC/5%CO2 for 20 hours. RNA was prepared from all treatment groups and analyzed for ERα mRNA level by qRT-PCR. Of the 12 tumors received to date, 6 displayed increased ERα mRNA levels after treatment with U0126. Collectively, these data are supportive of our hypothesis that there exists a population of ERα- tumors where upregulated growth factor signaling is directly involved in the generation of the ERα- phenotype by repressing ERα expression. Importanly, these data suggest that this reversible downregulation may be targeted clinically such that this repression can be reversed by inhibiting signaling through MAPK, resulting in re-expression of ERα and perhaps restoration of tamoxifen sensitivity." @default.
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• W2791781412 date "2006-04-15" @default.
• W2791781412 modified "2023-09-23" @default.
• W2791781412 title "Sphingosine kinase (SphK) mediates transactivation of the epidermal growth factor receptor (EGFR) by estrogen in breast cancer cells" @default.
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