The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development

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. [Display omitted] •Menopause, obesity, and cancer increase pro-inflammatory cytokines in human breast fat•Estrone stimulates and estradiol relieves the inflammation of obesity in vivo•Estrone cooperates with NFκB to induce inflammatory mediators, but estradiol does not•HSD17B14 increases intracellular estrone to drive inflammation and ER+ CSC expansion Slingerland and colleagues show that the major premenopausal estrogen, 17β-estradiol, and postmenopausal estrone play opposing roles to inhibit or drive, respectively, the tumor-promoting effects of inflammation and obesity. Estrone is pro-inflammatory and pro-oncogenic. It increases with obesity and stimulates expansion of stem-like cells in hormone-sensitive breast cancer to drive rapid tumor growth.