AUTHOR=Bezrookove Vladimir , Khan Imran A. , Nosrati Mehdi , Miller James R. , McAllister Sean , Dar Altaf A. , Kashani-Sabet Mohammed 

TITLE=BPTF promotes the progression of distinct subtypes of breast cancer and is a therapeutic target

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1011173

DOI=10.3389/fonc.2022.1011173

ISSN=2234-943X

ABSTRACT=<sec><title>Purpose</title><p>To assess the biomarker and functional role of the chromatin remodeling factor, bromodomain PHD finger transcription factor (BPTF), in breast cancer progression.</p></sec><sec><title>Methods</title><p><italic>BPTF</italic> copy number was assessed using fluorescence <italic>in situ</italic> hybridization. BPTF expression was regulated in breast cancer cells by shRNA/siRNA-mediated gene silencing and <italic>BPTF</italic> cDNA overexpression. The effects of regulating BPTF expression were examined on key oncogenic signaling pathways and on breast cancer cell proliferation, apoptosis, and cell cycle progression, as well as in xenograft models. The consequences of pharmacological bromodomain inhibition, alone or in combination with other targeted agents, on breast cancer progression were assessed in culture and in xenograft models.</p></sec><sec><title>Results</title><p><italic>BPTF</italic> copy number was gained in 34.1% and separately amplified in 8.2% of a breast cancer tissue cohort. Elevated <italic>BPTF</italic> copy number was significantly associated with increasing patient age and tumor grade and observed in both ER-positive and triple-negative breast cancer (TNBC) subtypes. <italic>BPTF</italic> copy number gain and amplification were also observed in The Cancer Genome Atlas (TCGA) breast cancer cohort. Stable shRNA-mediated silencing of <italic>BPTF</italic> significantly inhibited cell proliferation and induced apoptosis in TNBC and ER-positive human breast cancer cell lines. BPTF knockdown suppressed signaling through the phosphoinositide 3 kinase (PI3K) pathway, including reduced expression of phosphorylated AKT (Ser473), phosphorylated GSK-β (Ser9), and CCND1. These findings were confirmed following transient BPTF knockdown by a distinct siRNA in TNBC and ER-positive breast cancer cells. Stable suppression of BPTF expression significantly inhibited the in vivo growth of TNBC cells. Conversely, <italic>BPTF</italic> cDNA overexpression in TNBC and ER-positive breast cancer cells enhanced breast cancer cell proliferation and reduced apoptosis. <italic>BPTF</italic> targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Conclusion</title><p>These studies demonstrate BPTF activation in distinct breast cancer subtypes, identify pathways by which BPTF promotes breast cancer progression, and suggest BPTF as a rational target for breast cancer therapy.</p></sec>