Original Article

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ZBTB7A governs estrogen receptor alpha expression in breast cancer Free
Mary Ellen Molloy 1, Monika Lewinska 2, Amanda K. Williamson 1, Thanh Thao Nguyen 1,Gamze Kuser-Abali 1, Lu Gong 1, Jiawei Yan 1, John B. Little 1, Pier Paolo Pandolfi 3,and Zhi-Min Yuan 1,*
1 Department of Environmental Health, John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA
2 Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
3 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
*Correspondence to:Zhi-Min Yuan, E-mail: zyuan@hsph.harvard.edu
J Mol Cell Biol, Volume 10, Issue 4, August 2018, Pages 273-284  https://doi.org/10.1093/jmcb/mjy020
Keyword: Keywords: ZBTB7A, ERα, breast cancer, endocrine therapies

ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, has been shown to have a context-dependent role in cancer development and progression. The role of ZBTB7A in estrogen receptor alpha (ERα)-positive breast cancer is largely unknown. Approximately 70% of breast cancers are classified as ERα-positive. ERα carries out the biological effects of estrogen and its expression level dictates response to endocrine therapies and prognosis for breast cancer patients. In this study, we find that ZBTB7A transcriptionally regulates ERα expression in ERα-positive breast cancer cell lines by binding to the ESR1 promoter leading to increased transcription of ERα. Inhibition of ZBTB7A in ERα-positive cells results in decreased estrogen responsiveness as demonstrated by diminished estrogen-response element-driven luciferase reporter activity, induction of estrogen target genes, and estrogen-stimulated growth. We also report that ERα potentiates ZBTB7A expression via a post-translational mechanism, suggesting the presence of a positive feedback loop between ZBTB7A and ERα, conferring sensitivity to estrogen in breast cancer. Clinically, we find that ZBTB7A and ERα are often co-expressed in breast cancers and that high ZBTB7A expression correlates with improved overall and relapse-free survival for breast cancer patients. Importantly, high ZBTB7A expression predicts a more favorable outcome for patients treated with endocrine therapies. Together, these findings demonstrate that ZBTB7A contributes to the transcriptional program maintaining ERα expression and potentially an endocrine therapy-responsive phenotype in breast cancer.