Reversal of the Estrogen Receptor–Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response

Abstract

Purpose: In breast cancer, the presence of estrogen receptor a (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERa correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK)

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

“…Yet, when fulvestrant was withdrawn from the resistant cells, ERa expression was restored and in two out of three cell lines, expression of the estrogen responsive protein Bcl-2 followed, demonstrating the presence of a functional ERa in the resistant cells, in agreement with previously published data [34]. Other studies have shown that ErbB signaling in itself can suppress ERa expression and signaling in breast cancer cells and that inhibition of such ErbB signaling can reestablish ERa mediated signaling [18,19]. This was not the case in our model system where ERa signaling, as visualized by ERa and Bcl-2 expression, was repressed by the presence of fulvestrant in the medium, but unaffected by ErbB blockade with CI-1033 upon faslodex withdrawal.…”

“…When fulvestrant was withdrawn from the resistant cell lines for one week prior to initiation of experiments, ERa expression was increased in all three resistant cell lines [19,35]. In the present study, such an effect of ErbB blockade with CI-1033 was mainly expected in the fulvestrant withdrawn cultures, as the ERa protein is destabilized in the presence of fulvestrant.…”

“…MCF-7 cells could not sustain growth in presence of 2.5 lM CI-1033 for more than 2-3 weeks. It should be mentioned that MCF-7 cells could be subcultivated continuously with 1 lM CI-1033 with a weekly split ratio of between 10 and 15, compared to a split ratio for untreated MCF-7 cells of around [15][16][17][18][19][20]. Cultures treated with a combination of fulvestrant and 0.5 lM CI-1033 only showed a small increase in cell growth over the first week, followed by cell arrest and cell death, Fig.…”

“…In contrast, tumor cells which escape fulvestrant treatment leading to ERa downregulation are more likely to develop ERa independent upregulation of growth factor receptor signaling. Furthermore, preclinical data have suggested that increased growth factor expression and signaling through the ErbB receptors or downstream effectors may repress ERa expression and function [16][17][18][19], potentially making breast cancer cells less sensitive to endocrine therapy. Also, clinical data have indicated an inverse relationship between expression of at least the EGFR and ErbB2 receptors with ERa and their overexpression has been correlated to decreased antiestrogen sensitivity [20][21][22][23].…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The cells were found to have decreased ERα levels to endocrine therapy by down-regulation of Her-2/MAPK pathway and up-regulation of ERα. Inhibition of growth factor signaling directly with U0126, the MAPK/eRK inhibitor, or indirectly by upstream inhibition of EGFR by gefitinib or HER2 through trastuzumab has resulted in functional ERα expression in several ERα-negative breast cancer cell lines with varying levels of EGFR and HER2 expression including SUM 149 (high levels of EGFR), SUM 229 (EGFR overexpressor), and SUM 190 (EGFR and HER2 overexpressor) [278]. Treatment with these compounds sensitized all the breast cancer cells studied (except SUM 149 that has high NF-κB activity) to 4-hydroxytamoxifen.…”