No abstract

Background: Progesterone is an important hormone for development and normal function of the breast; however, its role in established breast cancers is less clear. Progestins have been implicated in regulating tumor cell growth, signaling, differentiation state, and stem/progenitor properties in breast cancer cells. High dose progestin treatment can be an effective therapy for some advanced breast tumors, through an unknown mechanism. Progesterone receptors (PRs) are considered positive prognostic indicators, although their levels vary considerably among luminal subtype breast tumors. Progestin/PR regulated genes in tumor cells have only been determined in cultured breast cancer cells and mouse mammary tumor models. Here we define tumor unique progestin-dependent growth effects and gene regulation profiles in patient-derived luminal breast tumor xenografts. Methods: For these studies, three luminal estrogen receptor (ER)+PR+ transplantable xenografts were used that were derived from one pleural effusion and two previously untreated primary tumors. All three tumors were estrogen dependent to various degrees and contained variable levels of ER (5–90%) and PR (5–90%). Tumors were grown in vivo under continuous placebo, estrogen, or estrogen plus progestin conditions for 8–10 weeks and growth parameters monitored. Gene expression profiles were determined from dissected tumors using Affymetrix® GeneChip human gene 1.1 ST microarrays and results analyzed using Partek Genomics Suite software. Specific gene regulation was confirmed by q-RT-PCR and immunohistochemistry. Results: Progestins had an inhibitory, neutral, and stimulatory effect on estrogen dependent growth in each of the three tumor lines. Accordingly, there was relatively little overlap in PR regulated genes between the three tumors. In the tumor in which progestin treatment had a potent anti-tumor effect, progestins were strong repressors of estrogen/ER-regulated genes. Gene expression patterns between the natural hormone progesterone and the synthetic drug MPA were compared in one tumor line and found to be mostly similar. The percent of PR+ tumor cells may have influenced the potency of gene regulation. Unique progestin regulated genes were discovered in this human tumor model system that were involved in immune response, cytokine signaling, and stem/progenitor cell features. Conclusions: Women with breast cancer are exposed to progestins naturally or through hormonal therapies and these may have a profound effect on tumor biology. In some tumors, progestins are potently anti-proliferative, while in others they elicit the opposite effect and potentiate estrogen induced tumor growth. The diversity of progestin-regulated genes in each tumor underscores the hormone's context dependent effects. Determining progestin dependent gene signatures in patient tumors may pinpoint appropriate candidates for progestin therapy in advanced tumors and/or provide a prognostic tool for predicting tumor progression. Funded by: NIH R01 CA140985 (C.A.S.), the Grohne Fund (P.K.), and the University of Colorado Cancer Center (C.A.S., P.K.) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-10.