Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women.
Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women.
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DOI：
10.1158/2159-8290.cd-11-0241
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发表时间：
2012-04
期刊：
影响因子：
28.2
通讯作者：
Dannenberg AJ
中科院分区：
文献类型：
--
作者：
Subbaramaiah K;Morris PG;Zhou XK;Morrow M;Du B;Giri D;Kopelovich L;Hudis CA;Dannenberg AJ
肥胖是绝经后妇女激素受体阳性乳腺癌的危险因素。雌激素的合成由CYP 19编码的芳香酶催化。我们先前表明，在存在特征性炎性病灶（乳房冠状结构，“CLS-B”）的超重和肥胖妇女的乳房组织中，芳香酶表达和活性增加。在临床前研究中，促炎性PGE 2是芳香化酶表达的决定因素。在此，我们提供的证据表明，考克斯-2衍生的PGE 2刺激cAMP→PKA信号转导通路激活CYP 19转录，导致超重和肥胖妇女乳腺组织中芳香化酶表达增加和孕酮受体水平升高。我们进一步证明，乳房内炎症（CLS-B指数）的测量比体重指数更好地与这些生物学终点相关。肥胖→炎症→芳香化酶轴可能导致激素受体阳性乳腺癌的风险增加和肥胖乳腺癌患者预后不良。
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 PGE2 is a determinant of aromatase expression. Here we provide evidence that COX-2-derived PGE2 stimulates the cAMP→PKA signal transduction pathway activating 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 biological endpoints 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 breast cancer patients.