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.

许多炎症相关疾病，包括癌症，在绝经后和肥胖的女性中增加。与 17β-雌二醇的抗炎作用相反，我们发现绝经后占主导地位的雌酮是促炎的。在人类乳腺脂肪细胞中，细胞因子表达会随着肥胖、更年期和癌症而增加。脂肪细胞：癌细胞相互作用刺激雌酮和 NFκB 依赖性促炎细胞因子上调。雌酮和 17β-雌二醇驱动的转录组不同。雌酮：ERα 刺激 NFκB 介导的细胞因子基因诱导；17β-雌二醇反对这一点。在肥胖小鼠中，雌酮增加，17β-雌二醇减轻炎症。雌酮在体内驱动更快速的 ER+ 乳腺癌生长. HSD17B14 将 17β-雌二醇转化为雌酮，与不良的 ER+ 乳腺癌预后相关。雌酮和 HSD17B14 上调炎症、ALDH1 活性和肿瘤球，而 17β-雌二醇和HSD17B14敲低则相反。最后，较高的瘤内雌酮：17β-雌二醇比率可增加体内肿瘤起始干细胞和 ER+ 癌症的生长。这些发现有助于解释为什么绝经后 ER+ 乳腺癌会随着肥胖而增加，并为预防和治疗提供新的策略。