ZBTB7A governs estrogen receptor alpha expression in breast cancer.

ZBTB7A, a member of the POZ/BTB and Kruppel (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 (ER alpha)-positive breast cancer is largely unknown. Approximately 70% of breast cancers are classified as ER alpha-positive. ERa 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 ER alpha expression in ER alpha-positive breast cancer cell lines by binding to the ESR1 promoter leading to increased transcription of ERa. Inhibition of ZBTB7A in ER alpha-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 ERa potentiates ZBTB7A expression via a posttranslational mechanism, suggesting the presence of a positive feedback loop between ZBTB7A and ERa, conferring sensitivity to estrogen in breast cancer. Clinically, we find that ZBTB7A and ER alpha 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 ERa expression and potentially an endocrine therapy-responsive phenotype in breast cancer.