Abstract
Both progesterone and the insulin-like growth factors (IGFs) are critically involved in mammary gland development and also in breast cancer progression. However, how the progesterone and IGF signaling pathways interact with each other to regulate breast cancer cell growth remains unresolved. In this study, we investigated progesterone regulation of IGF signaling components in breast cancer cells. We found that insulin receptor substrate-2 (IRS-2) levels were markedly induced by progesterone and the synthetic progestin R5020 in MCF-7 and other progesterone receptor (PR) positive breast cancer cell lines, whereas IRS-1 and the IGF-I receptor were not induced. The antiprogestin RU486 blocked the R5020 effect on IRS-2 expression. Ectopic expression of either PR-A or PR-B in C4-12 breast cancer cells (estrogen receptor and PR negative) showed that progestin upregulation of IRS-2 was mediated specifically by PR-B. The IRS-2 induction by R5020 occurred via an increase of IRS-2 mRNA levels. Furthermore, progestin treatment prior to IGF-I stimulation resulted in higher tyrosine-phosphorylated IRS-2 levels, increased binding of IRS-2 to Grb-2 and the PI3K regulatory subunit p85, and correspondingly enhanced ERK and Akt activation, as compared with IGF-I-only conditions. Taken together, our data suggest that IRS-2 may play an important role in crosstalk between progesterone and the IGFs in breast cancer cells.
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Acknowledgements
We thank Dr Gary Chamness and others in the Breast Center at Baylor College of Medicine for their helpful suggestions, technical assistance, and critical reading of the manuscript. We are grateful to Dr Kathryn Horwitz for providing the PR expression vectors. This work was supported by NIH grant CA94118 to A Lee and USAMRC grant DAMD17-01-1-0133 to X Cui.
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Cui, X., Lazard, Z., Zhang, P. et al. Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2. Oncogene 22, 6937–6941 (2003). https://doi.org/10.1038/sj.onc.1206803
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DOI: https://doi.org/10.1038/sj.onc.1206803
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