The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development
Metadatos
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Picón Ruiz, Manuel; Qureshi, Rehana; Aurrekoetxea-Rodriguez, Iskander; Nunes de Paiva, Vanessa; D’Amico, Massimo; Yoon, Hyunho; Radhakrishnan, Ramya; Morata-Tarifa, Cynthia; Ince, Tan; Lippman, Marc E.; Thaller, Seth R.; Rodgers, Steven E.; Kesmodel, Susan; Vivanco, Maria del Mar; Slingerland, Joyce M.Materia
Obesity Adipocytes Cytokines NFκB Estrone 17β-estradiol Inflammation ER+ breast cancer HSD17B14 Cancer stem cells Obesity
Fecha
2020-06-02Referencia bibliográfica
Picón Ruiz, M. et al. The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development. Cell Metab. 2020 Jun 2;31(6):1154-1172.e9
Patrocinador
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 845104Resumen
Many inflammation-associated diseases, including cancers, increase in women after menopause and with obesity. In contrast to anti-inflammatory actions of 17β-estradiol, we find estrone, which dominates after menopause, is pro-inflammatory. In human mammary adipocytes, cytokine expression increases with obesity, menopause, and cancer. Adipocyte:cancer cell interaction stimulates estrone- and NFκB-dependent pro-inflammatory cytokine upregulation. Estrone- and 17β-estradiol-driven transcriptomes differ. Estrone:ERα stimulates NFκB-mediated cytokine gene induction; 17β-estradiol opposes this. In obese mice, estrone increases and 17β-estradiol relieves inflammation. Estrone drives more rapid ER+ breast cancer growth in vivo. HSD17B14, which converts 17β-estradiol to estrone, associates with poor ER+ breast cancer outcome. Estrone and HSD17B14 upregulate inflammation, ALDH1 activity, and tumorspheres, while 17β-estradiol and HSD17B14 knockdown oppose these. Finally, a high intratumor estrone:17β-estradiol ratio increases tumor-initiating stem cells and ER+ cancer growth in vivo. These findings help explain why postmenopausal ER+ breast cancer increases with obesity, and offer new strategies for prevention and therapy.