Increased FOXA1 levels induce apoptosis and inhibit proliferation in FOXA1-low expressing basal breast cancer cells.

Abstract

The transcription factor FOXA1, which is a member of the forkhead class of DNA-binding proteins, interacts with Estrogen Receptor (ER) to mediate breast cancer progression. However, its role in basal breast cancer cells remains unclear. Although the overall levels of FOXA1 are decreased in the basal subtype of clinical TCGA breast cancer samples, the high levels of FOXA1 improve the survival of the patients from this subtype. This clinical phenomenon is consistent with that of FOXA1 stimulating apoptosis in FOXA1-low expressing basal breast cancer cells, such as MDA-MB-231, and MDA-MB-468 cells. In this study, we have constructed an inducible expression system of FOXA1 and demonstrated the induced expression of FOXA1 resulting in apoptosis and cell cycle arrest in MDA-MB-231 cells, as confirmed by transcriptomic analysis and in vivo tumor-grafted models. Furthermore, the low levels of Estrogen Receptor-1 (ESR1) are critical for FOXA1 in terms of its repressive roles in the cells, as evidenced by clinical data analysis indicating that the high levels of FOXA1 improve the survival of ESR1Low patients, but worsen the survival of ESR1High patients of breast cancer. When introduced into MDA-MB-231 cells, ESR1 counteracts the tumor suppressor roles of FOXA1 by altering the FOXA1-regulated gene transcription and the two proteins together maintain the tumor progression in vivo. Our cumulative results suggest that FOXA1 suppresses the basal breast cancer cells with FOXA1-low expressing status independent of ESR1 by inducing apoptosis and inhibiting cell proliferation, thereby implicating its potential therapeutic role in this group of breast cancer.

• Authors: Ke Xia, Wenqiang Huang, Xiaoyun Zhao, Xiaoqin Huang, Yan Chen, Li Yu, Yongjun Tan
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 12 Issue 6 Pg. 2641-2658 ( 2022) ISSN: 2156-6976 [Print] United States
• PMID: 35812039 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2022.