Abstract 2107: Aurora A kinase and progesterone receptor cross talk in breast cancer

Abstract

Abstract Breast cancer is the number one diagnosed cancer in women. Luminal breast cancers express steroid hormone receptors (SR) and these cases can be effectively treated with endocrine therapies that block estrogen receptor (ER) activity or estrogen synthesis. Unfortunately, at least 40% of women develop resistance to anti-estrogen treatments and progress to metastatic disease. One of the important transitions from hormone responsive (ER+/PR+ luminal A) to refractory (ER+ luminal B) disease involves the loss of progesterone receptor (PR) protein expression. However, data from large clinical trials showed that exposure to a synthetic progestin (MPA) and estrogen, but not estrogen alone, increased breast cancer incidence and tumor grade. These data, while somewhat controversial, implicate PR action in breast cancer development and progression. PR isoforms (A and B) are ligand-activated transcription factors, though they can be activated in the absence of progestin via signaling pathways commonly elicited downstream of growth factor receptors. We have shown that growth factor signaling (EGF or heregulin) through PR-B can initiate rapid proliferation and survival of breast cancer cells growing in soft-agar. PR-B is phosphorylated and hyperactived by mitogenic protein kinases, including MAPK, CDK2, and CK2. Notably, over-expression and activation of Aurora A kinase (downstream of MAPKs) is associated with invasive breast cancer and poor prognosis. We hypothesize that activation of protein kinases commonly overexpressed in breast cancer provide a context for aberrant PR activity, resulting in upregulation of Her2/erbB2 signaling, EMT, and increased expression of mammary stem-cell mediators (stemness). To model this process, we over-expressed oncogenic Raf1 in ER+/PR+ MCF-7 breast cancer cells. MCF-7-Raf1 cells exhibited constitutive activation of the MAPK pathway and upregulation of both ER and PR mRNA and protein relative to parental controls. Addition of progestin to MCF-7-Raf1 cells increased PR phosphorylation and soft agar growth that was blocked by MLN8237, an Aurora kinase inhibitor. Interestingly, passage of MCF-7-Raf1 cells as mouse xenografts (1GX) led to rapid tumor progression that was associated with increased Aurora A phosphorylation, loss of PR mRNA and protein, expression of epithelial-to-mesenchymal (EMT) markers, increased stemness, and tamoxifen resistance. These data suggest that Aurora A kinase and PR cross-talk may drive early breast cancer progression in response to growth promoting signals. Targeting this cross-talk with Aurora kinase inhibitors and anti-progestins, in conjunction with conventional estrogen-blocking therapies, may improve survival outcomes by preventing progression to endocrine failure. MCF-7-Raf1 and MCF-7-Raf-1 (1GX) cells may provide a useful model for the study of SR-loss during luminal A to luminal B transition. Citation Format: Katherine A. Leehy, Tarah M. Regan Anderson, Andrea R. Daniel, Antonino B. D'Assoro, Carol A. Lange. Aurora A kinase and progesterone receptor cross talk in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2014-2107