RT Journal Article
T1 The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development.
A1 Qureshi, Rehana
A1 Picon-Ruiz, Manuel
A1 Aurrekoetxea-Rodriguez, Iskander
A1 Nunes de Paiva, Vanessa
A1 D'Amico, Massimo
A1 Yoon, Hyunho
A1 Radhakrishnan, Ramya
A1 Morata-Tarifa, Cynthia
A1 Ince, Tan
A1 Lippman, Marc E
A1 Thaller, Seth R
A1 Rodgers, Steven E
A1 Kesmodel, Susan
A1 Vivanco, Maria Del Mar
A1 Slingerland, Joyce M
K1 17β-estradiol
K1 ER+ breast cancer
K1 HSD17B14
K1 NFκB
K1 adipocytes
K1 cancer stem cells
K1 cytokines
K1 estrone
K1 inflammation
K1 obesity
AB 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.
PB Cell Press
YR 2020
FD 2020-05-11
LK http://hdl.handle.net/10668/15673
UL http://hdl.handle.net/10668/15673
LA en
NO This work was supported by grants from the Florida Breast Cancer Foundation (J.M.S.), the Breast Cancer Research Foundation (J.M.S.), the NIH (1R01CA210440-01A1; J.M.S.), the Susan G. Komen Foundation (PDF16380958; M.P.-R. and J.M.S.), and the European Commission (MSCAIF-2018 845104; M.P.-R.). I.A.-R. and M.d.M.V. were supported by MINECO for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). We thank Lluis Morey for helpful discussions in the course of this work. We acknowledge assistance from the Oncogenomics, Biostatistics/Bioinformatics, and Biospecimen Shared Resources of Sylvester Comprehensive Cancer Center. Dr. Reuben Shaw is acknowledged for providing the pRL vector.
DS RISalud
RD Apr 7, 2025