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Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2

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Abstract

The role of estrogen receptor beta (ERβ) in breast cancer is unclear. ERβ is considered to have a protective role in breast cancer development based on findings demonstrating that ERβ expression inhibits ERα-mediated proliferation of breast cancer cells. We previously demonstrated that ERβ causes a ligand independent G2 cell cycle arrest in MCF-7 cells. To study the mechanisms of the ERβ-mediated G2 cell cycle arrest, we investigated its effects on the regulatory pathways responsible for the G2/M phase transition. We found that ERβ inhibits CDK1 activity, which is the critical determinant of the G2/M progression. CDK1 activity is modulated by both stimulatory and inhibitory factors. Cyclin B1 is the major activator of CDK1. ERβ inhibited the cell cycle-dependent stimulation of cyclin B1 mRNA and protein. GADD45A and BTG2 are two major inhibitors of CDK1, which have been implicated in breast tumor formation. Based on these findings, we explored if the expression pattern of GADD45A and BTG2 is affected by ERβ. We found that ERβ stimulates GADD45A and BTG2 mRNA levels. The induction of these two genes is caused by ERβ binding directly to these genes and recruiting c-jun and NCOA2. Our findings demonstrated that unliganded ERβ causes a G2 cell cycle arrest by inactivating CDK1 through the repression of cyclin B1 and stimulation of GADD45A and BTG2 expression. These results provide evidence that drugs that stimulate the production of unliganded ERβ may be effective new therapies to prevent breast cancer.

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Acknowledgments

We thank Xiaoyue Zhao for assistance with statistical analysis and Jan-Åke Gustafsson for providing plasmids. This work was supported by a grant from the American Cancer Society to D.C.L.

Conflict of interest

A.C. has nothing to declare. S.P., M.T., I.C., and E.S. are employees of Bionovo, Inc. D.C.L. is on the Scientific Advisory Board and has received financial support for research from Bionovo, Inc.

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Authors and Affiliations

  1. Departments of Obstetrics, Gynecology and Reproductive Sciences and Center for Reproductive Sciences, University of California, San Francisco, CA, 94143, USA

    Sreenivasan Paruthiyil, Aleksandra Cvoro & Dale C. Leitman

  2. Department of Nutritional Science and Toxicology, University of California, 44 Morgan Hall, Berkeley, CA, 94720, USA

    Dale C. Leitman

  3. Bionovo Inc., Emeryville, CA, 94608, USA

    Sreenivasan Paruthiyil, Mary Tagliaferri, Isaac Cohen & Emma Shtivelman

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  1. Sreenivasan Paruthiyil
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  2. Aleksandra Cvoro
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Correspondence to Dale C. Leitman.

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Paruthiyil, S., Cvoro, A., Tagliaferri, M. et al. Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast Cancer Res Treat 129, 777–784 (2011). https://doi.org/10.1007/s10549-010-1273-5

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  • DOI: https://doi.org/10.1007/s10549-010-1273-5

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