title: Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women.
abstract: 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 PGE(2) 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.
  
  
  CONCLUSIONS
  We show that obesity-associated inflammatory foci in the human breast are associated with elevated COX-2 levels and activation of the PGE2 → cAMP → PKA signal transduction pathway resulting in increased aromatase expression. These findings help to explain the link among obesity, low-grade chronic inflammation, and breast cancer with important clinical implications.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA. ksubba@med.cornell.edu
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Morris
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.forename: Monica
authors.initials: M
authors.lastname: Morrow
authors.forename: Baoheng
authors.initials: B
authors.lastname: Du
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D011980:Receptors, Progesterone / Q000378:metabolism; D012307:Risk Factors
chemical_list: D012333:RNA, Messenger; D011980:Receptors, Progesterone; D000242:Cyclic AMP; D001141:Aromatase; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone