Convergence of Progesterone and Epidermal Growth Factor Signaling in Breast Cancer: POTENTIATION OF MITOGEN-ACTIVATED PROTEIN KINASE PATHWAYS

Carol A Lange,Jennifer K Richer,Tianjie Shen,Kathryn B Horwitz

doi:10.1074/jbc.273.47.31308

Carol A Lange, Jennifer K Richer + Show 2 more

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https://doi.org/10.1074/jbc.273.47.31308

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Abstract

During late stages of breast cancer progression, tumors frequently acquire steroid hormone resistance with concurrent amplification of growth factor receptors; this alteration predicts a poor prognosis. We show here that following treatment with the progestin, R5020, breast cancer cells undergo a "biochemical shift" in the regulation of epidermal growth factor (EGF)-stimulated signaling pathways: R5020 potentiates the effects of EGF by up-regulating EGFR, c-ErbB2 and c-ErbB3 receptors, and by enhancing EGF-stimulated tyrosine phosphorylation of signaling molecules known to associate with activated type I receptors. Independently of EGF, R5020 increases Stat5 protein levels, association of Stat5 with phosphotyrosine-containing proteins, and tyrosine phosphorylation of JAK2 and Shc. Furthermore, progestins "prime" breast cancer cells for growth signals by potentiating EGF-stimulated p42/p44 mitogen-activated protein kinase (MAPK), p38 MAP kinase, and JNK activities. Although the levels of cyclin D1, cyclin E, and p21(WAF1), are up-regulated by R5020 alone, they are synergistically up-regulated by EGF in the presence of R5020. Up-regulation of cell cycle proteins by EGF is blocked by inhibition of p42/p44 MAPK only in the presence of R5020, supporting a shift in the regulation of these cell cycle mediators from MAPK-independent to MAPK-dependent pathways. In summary, progesterone selectively increases the sensitivity of key kinase cascades to growth factors, thereby priming cells for stimulation by latent growth signals. These data support a model in which breast cancer cell growth switches from steroid hormone to growth factor dependence.

Highlights

During late stages of breast cancer progression, tumors frequently acquire steroid hormone resistance with concurrent amplification of growth factor receptors; this alteration predicts a poor prognosis
We show here that following treatment with the progestin, R5020, breast cancer cells undergo a “biochemical shift” in the regulation of epidermal growth factor (EGF)-stimulated signaling pathways: R5020 potentiates the effects of EGF by up-regulating epidermal growth factor receptor (EGFR), c-ErbB2 and c-ErbB3 receptors, and by enhancing EGF-stimulated tyrosine phosphorylation of signaling molecules known to associate with activated type I receptors
Up-regulation of Type I Growth Factor Receptors by Progesterone—Because progestins can sensitize T47D breast cancer cells to the proliferative effects of EGF [26], and are known to increase expression of EGFR in certain breast cancer cell lines [22, 24, 25], we tested the effects of the progestin, R5020, on the expression of members of the type I growth factor receptor family in Progesterone receptor (PR)-positive T47D-YB cells and their PR-negative T47D-Y progenitors [27] (Fig. 2)

Summary

Introduction

During late stages of breast cancer progression, tumors frequently acquire steroid hormone resistance with concurrent amplification of growth factor receptors; this alteration predicts a poor prognosis. Of EGF, R5020 increases Stat5 protein levels, association of Stat5 with phosphotyrosine-containing proteins, and tyrosine phosphorylation of JAK2 and Shc. progestins “prime” breast cancer cells for growth signals by potentiating EGF-stimulated p42/p44 mitogenactivated protein kinase (MAPK), p38 MAP kinase, and JNK activities.

Results

Conclusion