Prostaglandin E₂ down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity– breast cancer connection

Obesity increases the risk of hormone receptor–positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E₂ (PGE₂) and hypoxia-inducible factor 1 (HIF-1) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1. Here, we sought to determine whether SIRT1 also plays a role in regulating aromatase expression. We demonstrate that reduced SIRT1 levels are associated with elevated levels of acetyl–HIF-1, HIF-1, and aromatase in breast tissue of obese compared with lean women. To determine whether these changes were functionally linked, ASCs were utilized. In ASCs, treatment with PGE₂, which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl–HIF-1 and HIF-1 levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE₂-mediated induction of acetyl–HIF-1, HIF-1, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1, blocked PGE₂-mediated increases in acetyl–HIF-1, HIF-1, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1 and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE₂ acted via prostaglandin E2 receptor 2 (EP₂) and EP₄ to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the SIRT1 promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1 contributes to the elevated levels of aromatase in breast tissues of obese women.