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

doi:10.1016/j.cmet.2020.05.008

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 journal › Article › peer-review

1 Scopus citations

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 language	English (US)
Pages (from-to)	1154-1172.e9
Journal	Cell Metabolism
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2020.05.008
State	Published - 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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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

The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development. / Qureshi, Rehana; Picon-Ruiz, Manuel; Aurrekoetxea-Rodriguez, Iskander; Nunes de Paiva, Vanessa; D'Amico, Massimo; Yoon, Hyunho; Radhakrishnan, Ramya; Morata-Tarifa, Cynthia; Ince, Tan; Lippman, Marc E.; Thaller, Seth R.; Rodgers, Steven E.; Kesmodel, Susan; Vivanco, Maria del Mar; Slingerland, Joyce M.

In: Cell Metabolism, Vol. 31, No. 6, 02.06.2020, p. 1154-1172.e9.

Research output: Contribution to journal › Article › peer-review

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, ME, Thaller, SR , Rodgers, SE, Kesmodel, S, Vivanco, MDM & Slingerland, JM 2020, 'The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development', Cell Metabolism, vol. 31, no. 6, pp. 1154-1172.e9. https://doi.org/10.1016/j.cmet.2020.05.008

Qureshi, Rehana ; Picon-Ruiz, Manuel ; Aurrekoetxea-Rodriguez, Iskander ; Nunes de Paiva, Vanessa ; D'Amico, Massimo ; Yoon, Hyunho ; Radhakrishnan, Ramya ; Morata-Tarifa, Cynthia ; Ince, Tan ; Lippman, Marc E. ; Thaller, Seth R. ; Rodgers, Steven E. ; Kesmodel, Susan ; Vivanco, Maria del Mar ; Slingerland, Joyce M. / The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development. In: Cell Metabolism. 2020 ; Vol. 31, No. 6. pp. 1154-1172.e9.

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

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.",

keywords = "17β-estradiol, ER+ breast cancer, HSD17B14, NFκB, adipocytes, cancer stem cells, cytokines, estrone, inflammation, obesity",

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

note = "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. ",

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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.

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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