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Growth Factor-mediated Signaling and Growth-negative MCF-7 Cells Restores both Estrogen and Insulin-like α in Estrogen Receptor α Re-expression of Estrogen Receptor Updated

Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptora (ERa) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ER a (C4 and C4-12 cells are ERa-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogenmediated signaling and growth was a consequence of loss of ER a, we re-expressed ERa in C4-12 cells by stable transfection with HA-tagged ERa. Three independent C4-12 ERa-HA clones expressed a functional ERa that (a) was down-regulated by estrogen, (b) conferred estrogeninduction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERa-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERa-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERa is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERa expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line.