Abstract LB412: SIRT1 deficiency limits steroid-hormones-induced growth-promoting signaling in the mammary epithelium

Abstract The female reproductive hormone estrogen (E2) plays a central role in breast cancer (BC) development, and about 70% of BC cases diagnosed in humans are estrogen receptor (ER)-positive breast cancer (ER+BC). Therefore, antiestrogens (which antagonize E2 binding to the receptor) and aromatase inhibitors (which block E2 synthesis) have been successfully used to treat ER+BC. However, a critical barrier to achieving the maximum benefit of hormonal therapy (HT) for ER+BC is that about 30-50% of ER+BC patients who take tamoxifen (TAM) develop resistance or are unresponsive to this therapy. The underlying molecular mechanism(s) of the loss of responsiveness to HT and the precise molecular mechanisms involved in E2-induced tumor growth are not fully understood. This lack of knowledge constitutes a significant impediment to designing a more effective therapeutic strategy for treating ER+BC. To understand the molecular mechanism of the anti-estrogen associated drug resistance, we screened molecular signaling pathways using two ER+BC cell lines (MCF7 and ZR75.1) that are tamoxifen sensitive (TAM-S) and tamoxifen-resistant (TAM-R). Our study provides evidence that Sirtuin type 1 (SIRT1), an NAD+-dependent type III histone deacetylase (HDAC) expression, is directly associated with TAM resistance. SIRT1 knockdown in TAM-R cell lines resensitizes to TAM treatment. Further, SIRT1 plays a critical role in E2-induced mitogenic signaling in ER+BC. SIRT1 physically interacts and functionally cooperates with estrogen receptor α (ERα) in human ER+BC. SIRT1 knockdown in human ER+BC cells reduced tumor growth by limiting E2-induced mitogenic signaling. Mammary gland-specific Sirt1 knockout impairs mammary gland development and tumor growth by limiting E2-target gene expression. Further, Sirt1 deficiency impairs E2-induced mammary stem cell (MaSC) and breast cancer stem cell (BCSC) self-renewal. Sirt1 deficiency significantly reduced the expression of E2-target genes, especially Amphiregulin (Areg), a member of the epidermal growth factor (EGF) family and a critical mediator of E2-signaling in mammary gland development with increased expression of the tumor suppressor Endomucin (Emcn), which inhibits the interaction between tumor cells and extracellular matrix. Overall, our study provides evidence showing that 1) SIRT1 could be the molecular transducer of steroid hormone-induced mitogenic signaling in ER+BC growth and metastasis; 2) SIRT1 inhibitors can be used as potential therapeutic drugs for ER+BC treatment and to circumvent drug resistance; 3) SIRT1 could play a key role in BCSC self-renewal and, therefore, a combination of SIRT1 inhibitors and HT could have a profound effect on ER+BC treatment and disease recurrence. Citation Format: Snigdha Devi Ganjikunta, Subha Sundaram, Nanditi Thangaraju, Sabarish Ramachandran, Sonia Batan, Jabuneesa Khanom, Kunal Kumar, Prasad Puttur, Muthusamy Thangaraju. SIRT1 deficiency limits steroid-hormones-induced growth-promoting signaling in the mammary epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB412.