%0 Journal Article
%A Qureshi, Rehana
%A Picon-Ruiz, Manuel
%A Aurrekoetxea-Rodriguez, Iskander
%A Nunes de Paiva, Vanessa
%A D'Amico, Massimo
%A Yoon, Hyunho
%A Radhakrishnan, Ramya
%A Morata-Tarifa, Cynthia
%A Ince, Tan
%A Lippman, Marc E
%A Thaller, Seth R
%A Rodgers, Steven E
%A Kesmodel, Susan
%A Vivanco, Maria Del Mar
%A Slingerland, Joyce M
%T The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development.
%D 2020
%U http://hdl.handle.net/10668/15673
%X 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.
%K 17β-estradiol
%K ER+ breast cancer
%K HSD17B14
%K NFκB
%K adipocytes
%K cancer stem cells
%K cytokines
%K estrone
%K inflammation
%K obesity
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