Journal of Steroid Biochemistry & Molecular Biology 85 (2003) 147–157 MAP kinases couple multiple functions of human progesterone receptors: degradation, transcriptional synergy, and nuclear association  Ming Qiu a , Carol A. Lange a,b,∗ a Department of Medicine, University of Minnesota Cancer Center, MMC 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA b Division of Hematology, Oncology, and Transplant, Department of Pharmacology, University of Minnesota Cancer Center, MMC 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA Abstract Breast cancers often have increased mitogen-activated protein kinase (MAPK) activity; this pathway influences breast cancer cell growth in part by targeting steroid hormone receptors. Bidirectional cross-talk between these two pathways is well documented; progestins increase the expression of type I growth factor receptors that couple to MAPK activation, and in turn, activation of p42 and p44 MAPKs increases ligand-dependent progesterone receptor (PR) transcriptional activity, and parodoxically, augments PR downregulation. Breast cancers that have become steroid hormone resistant often remain highly sensitive to growth factors. We believe that the mechanism of steroid hormone resistance is biochemically linked to the acquisition of growth factor responsiveness. Using in vitro models, we have established numerous regulatory links between signal transduction pathways elicited by peptide growth factors and PR. Of note is the role of phosphorylation of human PRs by MAPKs. Phosphorylation of PR on a key serine residue (Ser294) by MAPKs couples multiple receptor functions, including ligand-dependent PR downregulation by the ubiquitin–proteasome pathway, transcriptional synergy between progestins and growth factors, and nuclear localization of PR proteins. Linkage of these events suggests a mechanism for steroid hormone receptor “hypersensitivity” induced by growth factors. The uncoupling of these events during breast cancer progression is predicted to profoundly influence hormone responsiveness, as PR with altered stability may be driven primarily by upregulated growth factors. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Progesterone receptors; Phosphorylation; Mitogen-activated protein kinase; Ubiquitin; Breast cancer 1. Bidirectional regulation of epidermal growth factor receptor (EGFR) and progesterone receptor (PR) signaling in breast cancer The ovarian steroid hormones, estradiol and progesterone, are involved in breast cancer development, but at the time of diagnosis only one-third of tumors are steroid hormone dependent. As tumors progress, they are more likely to be- come resistant to endocrine therapies, yet often retain their nuclear steroid receptors. In fact, receptor loss or mutation accounts for only 10–20% of clinically observed steroid hormone-resistant tumors [1]. EGFR expression is signif- icantly associated with loss of steroid hormone sensitivity regardless of receptor status [2]. Thus, it has been postulated that in the vast majority of resistant tumors, control over growth is assumed by locally acting autocrine or paracrine  Presented at the 11th International Congress on Hormonal Steroids and Hormones and Cancer, ICHS & ICHC, Fukuoka, Japan, 21–25 October 2002. ∗ Corresponding author. Tel.: +1-612-626-0621; fax: +1-612-626-4915. E-mail address: lange047@tc.umn.edu (C.A. Lange). peptide growth factors; invasive cancers with the worst prog- noses are those that are growth factor receptor positive and steroid hormone resistant [3]. EGF may also play a role in steroid hormone responsive breast cancers. Several studies have documented a tran- scriptional and/or proliferative synergy between EGF and progesterone or estrogen [4,5], and that progesterone up- regulates EGFR expression on the cell surface [5–8]. We found that progesterone, acting through its nuclear steroid receptor, greatly potentiates the activities of several down- stream signaling pathways that are initiated by growth fac- tor receptors, including mitogen-activated protein kinases (MAPKs) [9,10]. Progestin-mediated biochemical changes in signaling molecules may contribute to a switch in the pro- liferative responsiveness of breast cancer cells from steroid hormone-dependent pathways to those activated by pep- tide growth factors [9,11]. Progesterone appears to act as a “priming factor” for the actions of secondary agents. In addi- tion to increasing high affinity EGFR numbers, progesterone affects the phosphorylation state of both EGFR and c-erbB2 receptors [5]. Sarup et al. [8] reported that both the syn- thetic progestin, R5020, and progesterone increased EGFR 0960-0760/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-0760(03)00221-8