Abstract B20: Targeting androgen receptor and vitamin D receptor in triple negative breast cancers

Abstract

Abstract Approximately 40,000 women die every year in the United States due to breast cancer. Clinically, breast cancers are categorized into three sub-types as Estrogen Receptor positive, Her2 positive and triple negative breast cancers (TNBC). Treatment of ER+ and Her2+ breast cancer has been very successful through targeted therapy, however TNBC lacks expression of these targeted proteins, Estrogen Receptor (ER) and Her2 (ER-/PR-/Her2-). TNBC tumors account for 10-15% of all breast tumors and they are typically associated with poorer prognosis compared to other breast cancer subtypes. Neo-adjuvant chemotherapy with Taxol, anthracyclines and Cisplatin are generally used as first-line treatment for TNBC patients. However, resistance to these agents is prevalent and less than 30% women diagnosed with TNBC survive beyond 5 years. This highlights the urgency to identify novel therapeutic targets and develop front line therapy for the treatment of TNBC. In an attempt to develop an innovative approach to classify and treat TNBC, we previously carried out an extensive study of different Hormone Receptors (HR) in 36 normal breast tissues and 1731 breast tumors (1259 ER+, 177 Her2+ and 258 TNBC) with a patient follow up extending beyond 25 years. We found that among the ~250 triple negative breast tumors examined, two-third of the TNBC tumors expressed Androgen Receptor (AR) and/or Vitamin D Receptor (VDR). Based on the expression patterns of these receptors, TNBCs are divided in three major groups: approximately one third of the TNBCs tumors were triple negative for ER, AR and VDR (HR0 TNBC), the remaining two thirds expressed VDR alone (HR1-v TNBC) or co-expressed AR and VDR (HR2-av TNBC). To evaluate the feasibility of targeting Androgen Receptor and Vitamin D Receptor in TNBC, we started with identifying cell line model systems with required expression patterns. We characterized hormone receptor expression in 22 different breast cancer cell lines at the protein level and TNBC lines with the required VDR and AR expression were identified. Treatment with AR and VDR agonists inhibited cell viability alone as well as in combination and further decreased cell viability when combined with chemotherapy drugs. The mechanisms through which these agonists induce decreased cell viability was through either G1 cell cycle arrest or apoptosis depending on the cell lines studied. In addition, a PCR-based human stem cell marker array showed changes in the established cancer stem cell markers on treatment with AR & VDR agonists. This was further confirmed by decrease in sphere formation efficiency as well as decrease in ALDH activity. Thus, hormone receptor therapy not only decrease cell viability but inhibit the cancer stem cell population of the cells. Citation Format: Ankita Thakkar, Bin Wang, Manuel Picon-Ruiz, Tan Ince. Targeting androgen receptor and vitamin D receptor in triple negative breast cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B20.