Integrative analyses identified gap junction beta‐2 as a prognostic biomarker and therapeutic target for breast cancer

Abstract

Background

Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.

Methods

We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.

Results

Gap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta‐2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta‐2 are rare in breast cancer. The gap junction beta‐2 transcription level in the p110α subunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type subgroup. Gap junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.

Conclusions

Gap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

Abstract

Gap junction beta‐2, a connexin protein, is overexpressed in various breast cancer subtypes and associated with poor prognosis. Notably, mutated Gap junction beta‐2 is localized on the tumor cell membrane, while somatic mutations and copy number variations are rare. Gap junction beta‐2 transcription levels were elevated in the p110α subunit of the phosphoinositide 3‐kinase (PI3K) mutant subgroup, linking it to the PI3K‐Akt signaling pathway, extracellular matrix–receptor interactions, focal adhesion, and proteoglycan regulation in cancer. Furthermore, Gap junction beta‐2 overexpression predicted resistance to PI3K and histone deacetylase inhibitors and correlated with immune cell infiltration, including CD8+ T cells, macrophages, neutrophils, and dendritic cells. Gap junction beta‐2 may serve as a dual therapeutic target for both targeted therapy and immunotherapy and could be a valuable predictor of breast cancer prognosis.