Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

Kirsten G.M. Aspros; Jodi M. Carter; Tanya L. Hoskin; Vera J. Suman; Malayannan Subramaniam; Michael J. Emch; Zhenqing Ye; Zhifu Sun; Jason P. Sinnwell; Kevin J. Thompson; Xiaojia Tang; Esther P.B. Rodman; Xiyin Wang; Adam W. Nelson; Igor Chernukhin; Feda H. Hamdan; Elizabeth S. Bruinsma; Jason S. Carroll; Martin E. Fernandez-Zapico; Steven A. Johnsen; Krishna R. Kalari; Haojie Huang; Roberto A. Leon-Ferre; Fergus J. Couch; James N. Ingle; Matthew P. Goetz; John R. Hawse

doi:10.1038/s41523-022-00387-0

Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

Kirsten G.M. Aspros, Jodi M. Carter, Tanya L. Hoskin, Vera J. Suman, Malayannan Subramaniam, Michael J. Emch, Zhenqing Ye, Zhifu Sun, Jason P. Sinnwell, Kevin J. Thompson, Xiaojia Tang, Esther P.B. Rodman, Xiyin Wang, Adam W. Nelson, Igor Chernukhin, Feda H. Hamdan, Elizabeth S. Bruinsma, Jason S. Carroll, Martin E. Fernandez-Zapico, Steven A. JohnsenKrishna R. Kalari, Haojie Huang, Roberto A. Leon-Ferre, Fergus J. Couch, James N. Ingle, Matthew P. Goetz, John R. Hawse

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

Abstract

Triple Negative Breast Cancer (TNBC) accounts for 15–20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ERβ) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ERβ and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ERβ was expressed in approximately 18% of TNBCs, and expression of ERβ was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ERβ formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NFκB/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERβ-mediated suppression of TNBC. Our findings indicate that ERβ+ tumors exhibit different characteristics compared to ERβ− tumors and demonstrate that ERβ functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.

Original language	English (US)
Article number	20
Journal	npj Breast Cancer
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41523-022-00387-0
State	Published - Dec 2022

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Pharmacology (medical)

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Aspros, K. G. M., Carter, J. M., Hoskin, T. L., Suman, V. J., Subramaniam, M., Emch, M. J., Ye, Z., Sun, Z., Sinnwell, J. P., Thompson, K. J., Tang, X., Rodman, E. P. B., Wang, X., Nelson, A. W., Chernukhin, I., Hamdan, F. H., Bruinsma, E. S., Carroll, J. S., Fernandez-Zapico, M. E., ... Hawse, J. R. (2022). Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer. npj Breast Cancer, 8(1), Article 20. https://doi.org/10.1038/s41523-022-00387-0

Aspros, KGM, Carter, JM, Hoskin, TL, Suman, VJ, Subramaniam, M, Emch, MJ, Ye, Z, Sun, Z, Sinnwell, JP, Thompson, KJ, Tang, X, Rodman, EPB, Wang, X, Nelson, AW, Chernukhin, I, Hamdan, FH, Bruinsma, ES, Carroll, JS, Fernandez-Zapico, ME , Johnsen, SA , Kalari, KR , Huang, H, Leon-Ferre, RA, Couch, FJ, Ingle, JN, Goetz, MP & Hawse, JR 2022, 'Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer', npj Breast Cancer, vol. 8, no. 1, 20. https://doi.org/10.1038/s41523-022-00387-0

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title = "Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer",

abstract = "Triple Negative Breast Cancer (TNBC) accounts for 15–20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ERβ) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ERβ and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ERβ was expressed in approximately 18% of TNBCs, and expression of ERβ was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ERβ formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NFκB/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERβ-mediated suppression of TNBC. Our findings indicate that ERβ+ tumors exhibit different characteristics compared to ERβ− tumors and demonstrate that ERβ functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.",

author = "Aspros, {Kirsten G.M.} and Carter, {Jodi M.} and Hoskin, {Tanya L.} and Suman, {Vera J.} and Malayannan Subramaniam and Emch, {Michael J.} and Zhenqing Ye and Zhifu Sun and Sinnwell, {Jason P.} and Thompson, {Kevin J.} and Xiaojia Tang and Rodman, {Esther P.B.} and Xiyin Wang and Nelson, {Adam W.} and Igor Chernukhin and Hamdan, {Feda H.} and Bruinsma, {Elizabeth S.} and Carroll, {Jason S.} and Fernandez-Zapico, {Martin E.} and Johnsen, {Steven A.} and Kalari, {Krishna R.} and Haojie Huang and Leon-Ferre, {Roberto A.} and Couch, {Fergus J.} and Ingle, {James N.} and Goetz, {Matthew P.} and Hawse, {John R.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41523-022-00387-0",

language = "English (US)",

volume = "8",

journal = "npj Breast Cancer",

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TY - JOUR

T1 - Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

AU - Aspros, Kirsten G.M.

AU - Carter, Jodi M.

AU - Hoskin, Tanya L.

AU - Suman, Vera J.

AU - Subramaniam, Malayannan

AU - Emch, Michael J.

AU - Ye, Zhenqing

AU - Sun, Zhifu

AU - Sinnwell, Jason P.

AU - Thompson, Kevin J.

AU - Tang, Xiaojia

AU - Rodman, Esther P.B.

AU - Wang, Xiyin

AU - Nelson, Adam W.

AU - Chernukhin, Igor

AU - Hamdan, Feda H.

AU - Bruinsma, Elizabeth S.

AU - Carroll, Jason S.

AU - Fernandez-Zapico, Martin E.

AU - Johnsen, Steven A.

AU - Kalari, Krishna R.

AU - Huang, Haojie

AU - Leon-Ferre, Roberto A.

AU - Couch, Fergus J.

AU - Ingle, James N.

AU - Goetz, Matthew P.

AU - Hawse, John R.

PY - 2022/12

Y1 - 2022/12

N2 - Triple Negative Breast Cancer (TNBC) accounts for 15–20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ERβ) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ERβ and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ERβ was expressed in approximately 18% of TNBCs, and expression of ERβ was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ERβ formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NFκB/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERβ-mediated suppression of TNBC. Our findings indicate that ERβ+ tumors exhibit different characteristics compared to ERβ− tumors and demonstrate that ERβ functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.

AB - Triple Negative Breast Cancer (TNBC) accounts for 15–20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ERβ) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ERβ and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ERβ was expressed in approximately 18% of TNBCs, and expression of ERβ was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ERβ formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NFκB/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERβ-mediated suppression of TNBC. Our findings indicate that ERβ+ tumors exhibit different characteristics compared to ERβ− tumors and demonstrate that ERβ functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.

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DO - 10.1038/s41523-022-00387-0

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JO - npj Breast Cancer

JF - npj Breast Cancer

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ER -

Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

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