Increased levels of COX-2 and prostaglandin E₂ contribute to elevated aromatase expression in inflamed breast tissue of obese women

Obesity is a risk factor for hormone receptor-positive breast cancer in postmenopausal women. Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. We previously showed that aromatase expression and activity are increased in the breast tissue of overweight and obese women in the presence of characteristic inflammatory foci [crown-like structures of the breast (CLS-B)]. In preclinical studies, proinflammatory prostaglandin E ₂ (PGE ₂) is a determinant of aromatase expression. We provide evidence that cyclooxygenase (COX)-2-derived PGE2 stimulates the cyclic AMP (cAMP)→PKA signal transduction pathway that activates CYP19 transcription, resulting in increased aromatase expression and elevated progesterone receptor levels in breast tissues from overweight and obese women. We further demonstrate that a measure of in-breast inflammation (CLS-B index) is a better correlate of these biologic end points than body mass index. The obesity→inflammation→aromatase axis is likely to contribute to the increased risk of hormone receptor- positive breast cancer and the worse prognosis of obese patients with breast cancer. SIGNIFICANCE: We show that obesity-associated inflammatory foci in the human breast are associated with elevated COX-2 levels and activation of the PGE ₂→cAMP→PKA signal transduction pathway resulting in increased aromatase expression. These findings help to explain the link among obesity, lowgrade chronic inflammation, and breast cancer with important clinical implications.