The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development 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. Obesity Adipocytes Cytokines NFκB Estrone 17β-estradiol Inflammation ER+ breast cancer HSD17B14 Cancer stem cells Obesity 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. 2022-03-24T08:04:22Z 2022-03-24T08:04:22Z 2020-06-02 info:eu-repo/semantics/article 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 http://hdl.handle.net/10481/73671 10.1016/j.cmet.2020.05.008 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess info:eu-repo/semantics/openAccess Atribución 3.0 España