Abstract 1777: Androgen receptor (AR) agonists inhibit AR- and estrogen-receptor-positive breast cancer

Abstract

Abstract Introduction: Breast cancer is the most common cancer diagnosed in women. About 13% of women will develop invasive breast carcinoma in their lifetime and it is estimated that about 280,000 new cases will be diagnosed in 2021. Seventy-percent of diagnosed breast cancers are estrogen receptor (ER)-positive and about 90% of the ER-positive breast cancers are androgen receptor (AR)-positive. We have previously shown that AR agonists inhibit ER-positive breast cancer growth by sequestering the pioneer-transcription factor FOXA1 from ER-cistrome. Tissue-selective AR modulators (SARMs) such as enobosarm are in clinical trials to treat ER-positive breast cancers. Since resistance is a major impediment to sutained treatment, it is important to identify new therapeutic strategies and their mechanisms of resistance. Here, we evaluated the possible mechanisms of resistance to AR agonists in ER-positive breast cancer. Description: ER-positive breast cancer cell line xenografts and patient-derived xenografts (PDX) were used as experimental models. Once tumors grew to ~100-300 mm3, mice were randomized and treated orally with vehicle or enobosarm (30 mg/kg/day). Animals were sacrificed after 4 weeks when the tumors responded to treatment and after 10 weeks once resistance developed to treatment. Tumor volumes were measured twice weekly and tumors were collected at sacrifice for further analyses. RNA-seq and ChIP-seq were performed on tumor tissues. Summary: AR agonists, enobosarm and dihydrotestosterone (DHT), inhibited the proliferation of ER-positive breast cancer cells ZR-75-1 and T47D. Transcriptome analysis revealed that AR agonists activate AR in ER-positive breast cancer cells and inhibit ER-target gene signature. AR agonists inhibited the growth of breast cancer cell line xenograft T47D and breast cancer PDXs HCI-7 that express wildtype ER, and HCI-13 and WHIM-23, two models that express Y537S mutant ER. Treatment of WHIM-23 and T47D xenograft for over ten weeks resulted in resistance and regrowth. AR agonist-sensitive and -resistant tumors were analyzed using RNA-seq, ChIP-seq, and ATAC-seq to understand the mechanism of resistance development. The results indicate that the prolonged activation of AR will result in resistance. These mechanisms of resistance can be utilized as possible therapeutic targets. Conclusion: These results suggest that the AR is a promising therapeutic target in the treatment of ER-positive breast cancer. However, resistance development is possible with AR agonists and the mechanism provides suggestions for future combination therapies. Disclosure: This work was supported by an NCI grant (CA229164 and CA229164S1 to RN) and by a DOD grant (W81XWH2110055 to RN). Citation Format: Sarah Asemota, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Ramesh Narayanan. Androgen receptor (AR) agonists inhibit AR- and estrogen-receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1777.