Abstract
Abstract Luminal breast cancers account for ~75% of all cases and while adjuvant hormone therapy targeting ERα has significantly improved overall survival for patients with ER+ tumors, acquired resistance remains a major clinical problem. Tamoxifen-resistant (TamR) breast cancer models show loss of IGF1R concomitant with increased insulin-induced growth, underpinned by insulin receptor (InsR) compensation for IGF1R loss. PR (gene name PGR) is an estrogen-regulated target gene whose expression is used as a clinical marker of ER activity. However, its de novo relevance to breast cancer is unclear. We have shown previously that post-translational modifications create unique PR species whose altered behavior drives an endocrine-resistant gene signature, in part by crosstalk with the IGFR pathway. We propose that phospho-PR target gene selectivity is mediated by cooperation between PR-B and InsR/IGF1R pathway components. Herein we show that phospho-PR-expressing T47D cells lose expression of IGF1R compared to control cells expressing WT PR-B. Furthermore, expression of the adapter protein IRS-1 requires PRB expression and these IRS-1+ cells were more sensitive to insulin in anchorage-dependent growth assays. Phospho-PR T47D cells exhibit increased ALDH+ and CD24-/CD44+ tumorsphere formation compared to wt PRB-expressing cells. Inhibitors targeting IRS-1 and InsR were used to test their requirement for tumorsphere growth and, surprisingly, IRS-1 perturbation reduced phospho-PRB but not wt PRB tumorsphere growth. Interestingly, IRS-1 replaces IGF1R in phospho-PRB-containing transcriptional complexes that are recruited to the CTSD promoter, which we previously identified as a phospho-PR target gene. Finally, breast cancer cells expressing phospho-PR species exhibited tamoxifen-resistant growth. Collectively our data suggest that phospho-PRB cooperates with IRS-1 downstream of the Ins/IGF1R system to promote outgrowth of endocrine-resistant cells that include ALDH+ stem-like cells capable of forming secondary tumorspheres in vitro. Targeting phospho-PR species in addition to the signaling components of PR-complexes may provide a means to block emergence of endocrine-resistant cancer cells during breast cancer progression. Citation Format: Amy R. Dwyer, Deepali Sachdev, Carol A. Lange. Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 949.
Published Version
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