Abstract 3511: Targeted epigenetic reprogramming reverts tumor progression in triple-negative breast cancer models by the activation of retinoic acid receptor alpha

INTRODUCTION: Triple negative breast cancer (TNBC) is associated with aggressiveness, early recurrence and poor prognosis and no other therapeutic alternative besides chemotherapy. The silencing of genes associated with cell differentiation in cancer is required for tumor progression. In this process the epigenetic modifications induced by aberrant control of the chromatin remodeling machinery in transformed cells plays a key role. Therefore, finding a mechanism to restore the expression of these genes by reverting the abnormal epigenetic modifications is an important task in the fight against cancer. We showed previously that the selective interference of the Sin39s PAH2 domain with Sin3 interaction domain (SID) mimicking peptides restored expression of E-cadherin, estrogen receptor and RARa target genes such as RARb and CRBP1 leading to cell differentiation and anti-tumor effect in TNBC cells. Here we studied whether the re-expression of retinoic acid receptors (RARs) induced by the small molecule C16 (SID decoy) can make TNBC cells sensitive to selective retinoid therapies. EXPERIMENTAL APPROACH: Human and mouse cell models of TNBC as well as MMTV-Myc oncomice were used to test the effects of the SID decoys on the induction of RAR signaling, cell proliferation, induction of differentiation in 3D cultures, expansion of the cancer stem cell compartment, atypical ductal hyperplasia (ADH), ductal carcinola in situ (DCIS), tumor development and metastatic dissemination. RESULTS: Our data show that C16 induced a differential expression of RARs, ∼10 fold upregulation of RARa2, RARbeta1/2, ∼10 fold downregulation of RARg1 and ∼30% increased production of retinoic acid (RA). The combination of C16 plus RARa agonists, AM80 (tamibarotene) or AM580 induced 75% inhibition of cell proliferation in 2D cultures, induced immature acini in 3D and impaired cancer stem cell proliferation inhibiting tumorsphere formation (∼65%) in vitro. In vivo, the combination of C16 and AM580 reduced 90% tumor growth and metastasis. Interestingly, the treatment of MMTV-Myc oncomice with C16 alone or in combination with AM80 prevented mammary gland hyperplasia, DCIS and delayed tumor development (80% tumor free survival, Kaplan-Meier analysis). CONCLUSION: As a whole, the epigenetic reprogramming of the TNBC cells is promising for design of therapies based on the use of RARa agonists to induce differentiation of the tumor cells; giving these patients a chance of an alternative or complementary therapy to chemotherapy regimens. Citation Format: Nidhi Bansal, Almudena Bosch, Boris A. Leibovitch, Keely Pierzchalski, Zhou Ming-Ming, Maureen Kane, Samuel Waxman, Eduardo Farias. Targeted epigenetic reprogramming reverts tumor progression in triple-negative breast cancer models by the activation of retinoic acid receptor alpha. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2015-3511