Oncotarget

Priority Research Papers:

ERβ inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer

Jordan M. Reese, Elizabeth S. Bruinsma, David G. Monroe, Vivian Negron, Vera J. Suman, James N. Ingle, Matthew P. Goetz and John R. Hawse _

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Oncotarget. 2017; 8:96506-96521. https://doi.org/10.18632/oncotarget.21787

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Abstract

Jordan M. Reese1, Elizabeth S. Bruinsma2, David G. Monroe2, Vivian Negron3, Vera J. Suman4, James N. Ingle5, Matthew P. Goetz1,5 and John R. Hawse2

1 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

3 Department of Pathology, Mayo Clinic, Rochester, MN, USA

4 Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

5 Department of Oncology, Mayo Clinic, Rochester, MN, USA

Correspondence to:

John R. Hawse, email:

Keywords: TNBC, ERβ, cell cycle, CDK, estrogen

Received: March 21, 2017 Accepted: September 16, 2017 Published: October 11, 2017

Abstract

Triple negative breast cancer (TNBC), which comprises approximately 15% of all primary breast cancer diagnoses, lacks estrogen receptor alpha, progesterone receptor and human epidermal growth factor receptor 2 expression. However, we, and others, have demonstrated that approximately 30% of TNBCs express estrogen receptor beta (ERβ), a nuclear hormone receptor and potential drug target. Treatment of ERβ expressing MDA-MB-231 cells with estrogen or the ERβ selective agonist, LY500307, was shown to result in suppression of cell proliferation. This inhibitory effect was due to blockade of cell cycle progression. In vivo, estrogen treatment significantly repressed the growth of ERβ expressing MDA-MB-231 cell line xenografts. Gene expression studies and ingenuity pathway analysis identified a network of ERβ down-regulated genes involved in cell cycle progression including CDK1, cyclin B and cyclin H. siRNA mediated knockdown or drug inhibition of CDK1 and CDK7 in TNBC cells resulted in substantial decreases in proliferation regardless of ERβ expression. These data suggest that the tumor suppressive effects of ERβ in TNBC result from inhibition of cell cycle progression, effects that are in part mediated by suppression of CDK1/7. Furthermore, these data indicate that blockade of CDK1/7 activity in TNBC may be of therapeutic benefit, an area of study that has yet to be explored.


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