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

AI Article Synopsis

  • Obesity raises the risk of hormone receptor-positive breast cancer in postmenopausal women due to increased aromatase levels in breast tissue.
  • Prostaglandin E (PGE) and hypoxia-inducible factor 1α (HIF-1α) are linked to higher aromatase expression by down-regulating SIRT1, a protein that normally inactivates HIF-1α.
  • Activating SIRT1 or inhibiting the protein PCAF can reduce the negative impact of PGE, helping control the elevated aromatase and potentially lowering breast cancer risk in obese women.

Article Abstract

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 E (PGE) and hypoxia-inducible factor 1α (HIF-1α) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1α. 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-1α, HIF-1α, 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 PGE, which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl-HIF-1α and HIF-1α levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE-mediated induction of acetyl-HIF-1α, HIF-1α, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1α, blocked PGE-mediated increases in acetyl-HIF-1α, HIF-1α, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1α and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE acted via prostaglandin E2 receptor 2 (EP) and EP to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1α contributes to the elevated levels of aromatase in breast tissues of obese women.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322870PMC
http://dx.doi.org/10.1074/jbc.RA118.005866DOI Listing

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