Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA; Department of Human Anatomy and Embryology, Faculty of Medicine, Biopathology and Medicine Regenerative Institute (IBIMER), and Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.
Cell Metab. 2020 Jun 2;31(6):1154-1172.e9. doi: 10.1016/j.cmet.2020.05.008.
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.
许多与炎症相关的疾病，包括癌症，在女性绝经后和肥胖时会增加。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具有促炎作用。在人类乳腺脂肪细胞中，随着肥胖、绝经和癌症的发生，细胞因子的表达会增加。脂肪细胞与癌细胞的相互作用会刺激雌酮和 NFκB 依赖性促炎细胞因子的上调。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-雌二醇则相反。在肥胖小鼠中，雌酮增加而 17β-雌二醇缓解炎症。雌酮在体内驱动更快的 ER+乳腺癌生长。将 17β-雌二醇转化为雌酮的 HSD17B14 与不良的 ER+乳腺癌结局相关。雌酮和 HSD17B14 上调炎症、ALDH1 活性和肿瘤球，而 17β-雌二醇和 HSD17B14 的敲低则相反。最后，肿瘤内高雌酮：17β-雌二醇比值增加肿瘤起始干细胞和 ER+癌症在体内的生长。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了新的策略。
