Miskin Rakshitha Pandulal, Warren Janine S A, Ndoye Abibatou, Wu Lei, Lamar John M, DiPersio C Michael
Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA.
Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
Cancers (Basel). 2021 Jan 27;13(3):480. doi: 10.3390/cancers13030480.
In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high expression correlates with poor survival. Moreover, high expression positively correlates with high expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.
在本研究中，我们证明整合素α3β1通过诱导转录因子脑-2（Brn-2）促进三阴性乳腺癌（TNBC）细胞的侵袭和转移特性。我们发现，RNA干扰介导的MDA-MB-231细胞中α3β1的抑制导致Brn-2 mRNA和蛋白表达降低以及该基因启动子活性降低。此外，RNA干扰靶向MDA-MB-231细胞中的Brn-2可降低体外侵袭和体内肺定植，并且外源性Brn-2表达部分恢复了α3β1被抑制的细胞的侵袭能力。α3β1促进MDA-MB-231细胞中Akt的磷酸化，用药物性Akt抑制剂（MK-2206）处理这些细胞可降低Brn-2表达和细胞侵袭，表明α3β1-Akt信号传导有助于Brn-2的诱导。对浸润性乳腺癌患者的RNA测序数据的分析显示，高表达与较差的生存率相关。此外，高表达与基底样乳腺癌中的高表达呈正相关，这与我们的实验结果一致，即α3β1在TNBC细胞中诱导Brn-2。总之，我们的研究证明了Brn-2在乳腺癌细胞中的促侵袭/促转移作用，并确定了整合素α3β1在调节Brn-2表达中的作用，从而揭示了整合素依赖性乳腺癌细胞侵袭的新机制。
