TY - JOUR
T1 - The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development
AU - Qureshi, Rehana
AU - Picon-Ruiz, Manuel
AU - Aurrekoetxea-Rodriguez, Iskander
AU - Nunes de Paiva, Vanessa
AU - D'Amico, Massimo
AU - Yoon, Hyunho
AU - Radhakrishnan, Ramya
AU - Morata-Tarifa, Cynthia
AU - Ince, Tan
AU - Lippman, Marc E.
AU - Thaller, Seth R.
AU - Rodgers, Steven E.
AU - Kesmodel, Susan
AU - Vivanco, Maria del Mar
AU - Slingerland, Joyce M.
N1 - Funding Information:
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 (MSCA-IF-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. Conceptualization, J.M.S. M.E.L. R.Q. and M.P.-R.; Methodology, J.M.S. M.P.-R. and R.Q.; Investigation, R.Q. M.P.-R. M.D. H.Y. R.R. C.M.-T. V.N.d.P. T.I. and I.A.-R.; Validation, M.P.-R. R.Q. and J.M.S.; Formal Analysis, R.Q. M.P.-R. and J.M.S. Writing ? Original Draft, M.P.-R. J.M.S. and R.Q.; Writing ? Review & Editing, J.M.S. M.P.-R. and R.Q.; Funding Acquisition and Resources, J.M.S. M.P.-R. and M.d.M.V. The authors declare no competing interests.
Funding Information:
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 ( MSCA-IF-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.
Publisher Copyright:
© 2020
PY - 2020/6/2
Y1 - 2020/6/2
N2 - 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.
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.
KW - 17β-estradiol
KW - ER+ breast cancer
KW - HSD17B14
KW - NFκB
KW - adipocytes
KW - cancer stem cells
KW - cytokines
KW - estrone
KW - inflammation
KW - obesity
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U2 - 10.1016/j.cmet.2020.05.008
DO - 10.1016/j.cmet.2020.05.008
M3 - Article
C2 - 32492394
AN - SCOPUS:85085522822
VL - 31
SP - 1154-1172.e9
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 6
ER -