Bezrookove Vladimir, Khan Imran A, Nosrati Mehdi, Miller James R, McAllister Sean, Dar Altaf A, Kashani-Sabet Mohammed
California Pacific Medical Center Research Institute, San Francisco, CA, United States.
Front Oncol. 2022 Nov 30;12:1011173. doi: 10.3389/fonc.2022.1011173. eCollection 2022.
To assess the biomarker and functional role of the chromatin remodeling factor, bromodomain PHD finger transcription factor (BPTF), in breast cancer progression.
copy number was assessed using fluorescence hybridization. BPTF expression was regulated in breast cancer cells by shRNA/siRNA-mediated gene silencing and 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.
copy number was gained in 34.1% and separately amplified in 8.2% of a breast cancer tissue cohort. Elevated 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. copy number gain and amplification were also observed in The Cancer Genome Atlas (TCGA) breast cancer cohort. Stable shRNA-mediated silencing of 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, cDNA overexpression in TNBC and ER-positive breast cancer cells enhanced breast cancer cell proliferation and reduced apoptosis. targeting with the bromodomain inhibitor bromosporine, alone or in combination with the PI3K pathway inhibitor gedatolisib, produced significant anti-tumor effects against TNBC cells and .
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.
评估染色质重塑因子溴结构域PHD指转录因子（BPTF）在乳腺癌进展中的生物标志物及功能作用。
使用荧光杂交评估拷贝数。通过shRNA/siRNA介导的基因沉默和cDNA过表达在乳腺癌细胞中调节BPTF表达。研究调节BPTF表达对关键致癌信号通路以及乳腺癌细胞增殖、凋亡和细胞周期进程的影响，并在异种移植模型中进行研究。在培养物和异种移植模型中评估单独或与其他靶向药物联合使用的溴结构域药理抑制对乳腺癌进展的影响。
在一组乳腺癌组织中，34.1%的样本存在拷贝数增加，8.2%的样本存在单独扩增。拷贝数升高与患者年龄增加和肿瘤分级显著相关，且在雌激素受体阳性（ER阳性）和三阴性乳腺癌（TNBC）亚型中均有观察到。在癌症基因组图谱（TCGA）乳腺癌队列中也观察到拷贝数增加和扩增。稳定的shRNA介导的BPTF沉默显著抑制TNBC和ER阳性人乳腺癌细胞系中的细胞增殖并诱导凋亡。BPTF敲低抑制了通过磷脂酰肌醇3激酶（PI3K）途径的信号传导，包括磷酸化AKT（Ser473）、磷酸化GSK-β（Ser9）和CCND1表达的降低。在TNBC和ER阳性乳腺癌细胞中通过不同的siRNA短暂敲低BPTF后，这些发现得到了证实。稳定抑制BPTF表达显著抑制TNBC细胞的体内生长。相反，在TNBC和ER阳性乳腺癌细胞中过表达BPTF cDNA可增强乳腺癌细胞增殖并减少凋亡。单独或与PI3K途径抑制剂吉地替尼联合使用溴结构域抑制剂溴osporine靶向BPTF，对TNBC细胞产生了显著的抗肿瘤作用。
这些研究证明了BPTF在不同乳腺癌亚型中的激活，确定了BPTF促进乳腺癌进展的途径，并表明BPTF是乳腺癌治疗的合理靶点。
