Progestin Gene Regulation in Dual PR/AR Positive Breast Tumors

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-296
Jessica A Finlay-Schultz, Peter Hendricks, Rachel B Rosen, Kale Flory, Anthony Elias, Britta M Jacobsen, Peter Kabos and Carol A Sartorius*
Univ of Colorado Anschutz Medical Campus, Aurora, CO
Progesterone receptors (PR) are expressed in half of all breast cancers and generally signify positive prognosis as a marker of functional estrogen receptors (ER), the target of endocrine therapies. Progestins often block estrogen mediated gene transcription, but also regulate independent sets of genes, although little is know about their identity in solid tumors. Confounding the issue is that the majority of PR+ tumors also express androgen receptors (AR), and the two receptors bind to similar response elements in the genome. Additionally, some progestins have partial binding affinity for AR and can elicit androgenic activity. The goal of this study was to determine gene regulation by progestins in whole tumor models of ER+PR+AR+ breast cancers. For these studies we used two transplantable patient-derived breast tumor xenografts that are ER+ and estrogen responsive; tumor PE4 is >90% positive for each of ER, PR, and AR (PR=AR), while tumor PT15 has low ER (10%) and PR (5%), but higher AR (30%) expression (AR>PR). Tumors were partitioned into female NOD/SCID/ILIIrg−/− mice supplemented with placebo, 17β-estradiol alone (E), E + the natural hormone progesterone, or E + the synthetic progestin medroxyprogesterone acetate (MPA). Transcriptomes were measured from whole tumor pieces using Affymetrix HuGene 1.1 Array strips and results analyzed using Partek Genomics Suite software. P and MPA -regulated genes were calculated as those differentially expressed (p<0.05, FC>1.5) compared to E alone.

Results: P and MPA regulated a similar number of genes in PE4 (AR=PR), and both progestins reversed expression of ~30% of ER regulated genes. This coincided with a significant decrease in PE4 tumor growth with E+P or E+MPA compared to E alone. By contrast, MPA regulated four times as many genes as P in PT15 (AR>PR), and reversed few E regulated genes. PT15 grew significantly larger with E+MPA but not E+P, compared to E alone. Notably, <1% of P and <5% of MPA regulated genes overlapped between the two tumors. P and MPA regulated genes from either PE4 or PT15 shared <5% overlap with P and MPA regulated genes mapped in PR-rich T47D breast cancer cell lines and tumors (PR>AR). We conclude from these data: 1) progestins regulate unique gene cohorts in individual breast tumors, 2) the balance of PR vs. AR expression in breast tumors dictates the transcriptional response to MPA, and 3) the tumor specific gene network regulated by progestins may dictate whether they synergize or antagonize E-dependent growth. These data underscore the complexity of progestin response in heterogeneous steroid receptor expressing breast tumors and explain why strategies to uniformly agonize or antagonize PR have not been successful; natural or synthetic ligands with a more targeted response may offer new endocrine treatment options for receptor positive breast cancers.

Nothing to Disclose: JAF, PH, RBR, KF, AE, BMJ, PK, CAS

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: Supported by: NIH R01 CA14095A2 (C.A.S.); K08CA164048 (P.K.); the Grohne Fund (P.K.)