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Endocrinology |
in Estrogen Receptor -negative MCF-7 Cells Restores both Estrogen and Insulin-like Growth Factor-mediated Signaling and Growth1
Breast Center, Department of Medicine and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 [S. O., P. Z., R. L. G., X. S., C. K. O., A. V. L.], and Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri 65211 [E. M. C., W. V. W.]
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 receptor 
(ER) 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 (C4 and C4-12 cells are ER-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 estrogen-mediated signaling and growth was a consequence of loss of ER, we re-expressed ER in C4-12 cells by stable transfection with HA-tagged ER. Three independent C4-12 ER-HA clones expressed a functional ER that (a) was down-regulated by estrogen, (b) conferred estrogen-induction 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, ER-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ER-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 ER is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ER expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line.
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