ZBTB7A governs estrogen receptor alpha expression in breast cancer

TY - JOUR

T1 - ZBTB7A governs estrogen receptor alpha expression in breast cancer

AU - Molloy, Mary Ellen

AU - Lewinska, Monika

AU - Williamson, Amanda K.

AU - Nguyen, Thanh Thao

AU - Kuser-Abali, Gamze

AU - Gong, Lu

AU - Yan, Jiawei

AU - Little, John B.

AU - Pandolfi, Pier Paolo

AU - Yuan, Zhi Min

PY - 2018

Y1 - 2018

N2 - ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, has been shown to have a contextdependent 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 posttranslational 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.

AB - ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, has been shown to have a contextdependent 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 posttranslational 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.

KW - breast cancer

KW - endocrine therapies

KW - ERα

KW - ZBTB7A

U2 - 10.1093/jmcb/mjy020

DO - 10.1093/jmcb/mjy020

M3 - Journal article

C2 - 30265334

AN - SCOPUS:85054389790

SN - 1674-2788

VL - 10

SP - 273

EP - 284

JO - Journal of Molecular Cell Biology

JF - Journal of Molecular Cell Biology

IS - 4

ER -