Birgersson Madeleine, Chi Mengna, Miller Chrissy, Brzozowski Joshua S, Brown Jeffrey, Schofield Lachlan, Taylor Olivia G, Pearsall Elizabeth A, Hewitt Jasmine, Gedye Craig, Lincz Lisa F, Skelding Kathryn A
Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia.
School of Biomedical Sciences and Pharmacy, Karolinska Intitutet, Solna, Sweden.
Front Oncol. 2021 Apr 22;11:656120. doi: 10.3389/fonc.2021.656120. eCollection 2021.
Brain and Acute Leukemia, Cytoplasmic (BAALC) is a protein that controls leukemia cell proliferation, differentiation, and survival and is overexpressed in several cancer types. The gene is located in the chromosomal region 8q22.3, an area commonly amplified in breast cancer and associated with poor prognosis. However, the expression and potential role of BAALC in breast cancer has not widely been examined. This study investigates BAALC expression in human breast cancers with the aim of determining if it plays a role in the pathogenesis of the disease. BAALC protein expression was examined by immunohistochemistry in breast cancer, and matched lymph node and normal breast tissue samples. The effect of gene expression on overall survival (OS), disease-free and distant metastasis free survival (DMFS) was assessed using the Kaplan-Meier Plotter (n=3,935), the TCGA invasive breast carcinoma (n=960) and GOBO (n=821) data sets. Functional effects of BAALC expression on breast cancer proliferation, migration and invasion were determined . We demonstrate herein that BAALC expression is progressively increased in primary and breast cancer metastases when compared to normal breast tissue. Increased mRNA is associated with a reduction in DMFS and disease-free survival, but not OS, in breast cancer patients, even when corrected for tumor grade. We show that overexpression of BAALC in MCF-7 breast cancer cells increases the proliferation, anchorage-independent growth, invasion, and migration capacity of these cells. Conversely, siRNA knockdown of BAALC expression in Hs578T breast cancer cells decreases proliferation, invasion and migration. We identify that this BAALC associated migration and invasion is mediated by focal adhesion kinase (FAK)-dependent signaling and is accompanied by an increase in matrix metalloproteinase (MMP)-9 but not MMP-2 activity . Our data demonstrate a novel function for BAALC in the control of breast cancer metastasis, offering a potential target for the generation of anti-cancer drugs to prevent breast cancer metastasis.
脑与急性白血病细胞质蛋白（BAALC）是一种控制白血病细胞增殖、分化和存活的蛋白质，在多种癌症类型中过表达。该基因位于染色体8q22.3区域，这一区域在乳腺癌中常发生扩增且与预后不良相关。然而，BAALC在乳腺癌中的表达及潜在作用尚未得到广泛研究。本研究调查BAALC在人类乳腺癌中的表达情况，旨在确定其是否在该疾病的发病机制中发挥作用。通过免疫组织化学检测乳腺癌、配对的淋巴结及正常乳腺组织样本中BAALC蛋白的表达。利用Kaplan-Meier Plotter（n = 3935）、TCGA浸润性乳腺癌（n = 960）和GOBO（n = 821）数据集评估基因表达对总生存期（OS）、无病生存期和无远处转移生存期（DMFS）的影响。确定BAALC表达对乳腺癌增殖、迁移和侵袭的功能影响。我们在此证明，与正常乳腺组织相比，原发性乳腺癌和乳腺癌转移灶中BAALC的表达逐渐增加。乳腺癌患者中，即使校正了肿瘤分级，BAALC mRNA水平升高仍与DMFS和无病生存期缩短相关，但与OS无关。我们发现，在MCF-7乳腺癌细胞中过表达BAALC可增加这些细胞的增殖、非锚定依赖性生长、侵袭和迁移能力。相反，在Hs578T乳腺癌细胞中敲低BAALC表达可降低细胞增殖、侵袭和迁移能力。我们确定，BAALC相关的迁移和侵袭是由粘着斑激酶（FAK）依赖性信号传导介导的，且伴随着基质金属蛋白酶（MMP）-9活性增加，但MMP-2活性未增加。我们的数据证明了BAALC在控制乳腺癌转移方面的新功能，为开发预防乳腺癌转移的抗癌药物提供了潜在靶点。
