RF05 | PSUN341 Role of sirtuins in breast cancer cells response to Fulvestrant
Authors: Sengupta Surojeet , de Oliveira Karla , Jin Lu , Clarke Robert 
Published: November 2022

Endocrine therapies reduce glucose and glutamine uptake and total cellular ATP production in breast cancer (BC) cells, resulting in changes in cellular nutrient balance that could lead to cell cycle arrest and to cell death. Understanding the ability of cells to bypass these metabolic effects is fundamental to understand acquisition of endocrine resistance and cross-resistance to other drugs by BC cells.

Sirtuins (SIRTs) are NAD+-dependent deacylases involved in a variety of cellular processes, including metabolism and stress responses. SIRT1 deacetylates histones and transcription factors, and regulates glucose metabolism through TORC2, PGC1α, FOXO1. SIRT3 modulates mitochondria adaptation to conditions of low energy input by promoting the production of energy from sources different from glucose. SIRT3 mediates metabolic reprogramming by also destabilizing HIF-1α, regulating glycoytic gene expression. SIRT 3 regulation of the mitochondrial unfolded protein response and mitophagy machinery has been described. SIRT3expression is higher in early (≤3 years) vs. late (≥5 years) recurrences (measure of resistance vs. dormancy) in 4 clinical datasets. Using Differential Dependency Network analysis to compare the wiring of the SIRTs and key metabolism-related genes in matched antiestrogen- sensitive vs. resistant BC cells, guided by gene related to the nicotinate and nicotinamide metabolism, and associated with clinical outcome in ER+ patients treated with an endocrine therapy, we identified several novel signaling hubs including: CDKN2A (p16) Hub, linking SIRT3 to cell proliferation; TP53 Hub, linking SIRT5 to clinical resistance to aromatase inhibitors, cell survival and proliferation; ATM Hub that comprises ATM/SIRT2/SIRT4/HIF1A and may functionally link endocrine resistance to chemoresistance, consistent with the relatively poor responses of ER+ BC to cytotoxic drugs. Ability of SIRTs to sense and respond to changes in energy could provide a mechanism for an acquired drug-resistant phenotype enabled by epigenetically maintained changes in genes that control metabolism.Using endocrine sensitive (LCC1) and resistant (LCC9) BC cells, we confirmed the higher expression of SIRT1 and 3 in LCC9, compared to LCC1 cells. Upregulation of SIRT3 and SIRT5 expression within 24 hrs of Fulvestrant (ICI; 1 µM) treatment (p=0.0176) was observed in LCC1, but not in LCC9 cells. Conversely, treatment with 17β-estradiol (10 nM) did not significantly affect SIRT3 or SIRT5 expression within 72h in either LCC1 or LCC9 cells. Silencing of SIRT3 induced cell death, reducing growth of LCC9 after 72h of ICI treatment, compared to the untreated control, but no G1/G2 phase arrest in cell cycle was observed during same treatment. In ER+ BC patients, lower expression of SIRT3 is associated with poor relapse free survival (RFS) (HR=0.57; CI=0.43-0.76); p= 7.7x 10-5) whereas higher expression of SIRT5 is associated with poor RFS (HR=2.5; CI=0.99-6.59; p=4.4×10-2). These data indicate an involvement of SIRTs in response to Fulvestrant by BC cells and will be more investigated.

Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.