The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer

Abstract

Gap junction transmembrane channels allow the transfer of small molecules between the cytoplasm of adjacent cells. They are formed by proteins named connexins (Cxs) that have long been considered as a tumor suppressor. This widespread view has been challenged by recent studies suggesting that the role of Connexin 43 (Cx43) in cancer is tissue- and stage-specific and can even promote tumor progression. High throughput profiling of invasive breast cancer has allowed for the construction of subtyping schemes that partition patients into at least four distinct intrinsic subtypes. This study characterizes Cx43 expression during cancer progression with each of the tumor subtypes using a compendium of publicly available gene expression data. In particular, we show that Cx43 expression depends greatly on intrinsic subtype. Tumor grade also co-varies with patient subtype, resulting in Cx43 co-expression with grade in a subtype-dependent manner. Better survival was associated with a high expression of Cx43 in unstratified and luminal tumors but with a low expression in Her2e subtype. A better understanding of Cx43 regulation in a subtype-dependent manner is needed to clarify the context in which Cx43 is associated with tumor suppression or cancer progression.

Functional variation of SLC52A3 rs13042395 predicts survival of Chinese gastric cancer patients

“…Researchers already confirmed that the connexin gene family played a complicated role in tumorigenesis and progression 21 . Recently researcher found that GJA1 was associated in glioblastoma cancer cells apoptosis and promote the progression and invasion in breast cancer cells 22,23 . Few research about GJA1 was conducted in GCa, one of them suggested that overexpression of GJA1 leads to decreased ability of colony forming and invasive ability in BGC‐823 cells, 24 which was consistent with our research results.…”

Cx43 Expression Correlates with Breast Cancer Metastasis in MDA-MB-231 Cells In Vitro, In a Mouse Xenograft Model and in Human Breast Cancer Tissues

“…There was no differential Cx43 expression between the different subtypes and a correlation between Cx43 and ER/PR/erbB2 could not be established in the examined tissues [28]. Consistently, Busby et al, 2018 report that Cx43 expression depends greatly on intrinsic subtype [52]. Most importantly, Arora et al, 2018 report that decreased GJA1 expression leads to worse survival outcomes in patients, in several cancers including breast cancer [53], and another recent study reported Cx43 as an independent predictor of breast cancer patient prognosis and outcome [54].…”

Emerging roles for multifunctional ion channel auxiliary subunits in cancer

“…GlialCAM expression is also sufficient for reducing Notch-mediated invasion and migration in prostate cancer cells [ 282 ]. Lastly, GlialCAM stabilises connexin-43 at cell-cell gap junctions [ 287 ], connexin-43 being a potential tumour suppressor itself [ 288 , 289 ]. In summary, GlialCAM has a strong anti-proliferative influence when expressed in cancer cells, which could underpin its role as a tumour suppressor.…”