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

Rehana Qureshi, Manuel Picon-Ruiz, Iskander Aurrekoetxea-Rodriguez, Vanessa Nunes de Paiva, Massimo D'Amico, Hyunho Yoon, Ramya Radhakrishnan, Cynthia Morata-Tarifa, Tan Ince, Marc E. Lippman, Seth R. Thaller, Steven E. Rodgers, Susan Kesmodel, Maria del Mar Vivanco, Joyce M. Slingerland

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1154-1172.e9
JournalCell Metabolism
Volume31
Issue number6
DOIs
StatePublished - Jun 2 2020

Keywords

  • 17β-estradiol
  • ER+ breast cancer
  • HSD17B14
  • NFκB
  • adipocytes
  • cancer stem cells
  • cytokines
  • estrone
  • inflammation
  • obesity

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Qureshi, R., Picon-Ruiz, M., Aurrekoetxea-Rodriguez, I., Nunes de Paiva, V., D'Amico, M., Yoon, H., Radhakrishnan, R., Morata-Tarifa, C., Ince, T., Lippman, M. E., Thaller, S. R., Rodgers, S. E., Kesmodel, S., Vivanco, M. D. M., & Slingerland, J. M. (2020). The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development. Cell Metabolism, 31(6), 1154-1172.e9. https://doi.org/10.1016/j.cmet.2020.05.008