BC is a life-threatening disease for females, especially Her2 + BC with rapid tumor progression, easy recurrence and metastasis and poor prognosis. Despite of the great progress in Her2 + BC treatment options in the past decades, much more remains to be done, more cancer-driving genes need to be identified. Therefore it is critical to find more of the potential genes involved in the development and progression of Her2 + BC.
In this work, we used WGCNA to dynamically study genes co-expression in Her2 + BC, Luminal-A BC, and Luminal-B BC, and to explore the related modules and hub genes. We concluded that the skyblue3 module had the highest correlation with Her2 + BC. Skyblue3 module related to Her2 + BC has well defined functions including nuclear-transcribed mRNA catabolic process, cytosol, and oxidoreductase activity. In the genes of the skyblue3 module, PGAP3, PPP1R1B, PNMT, ERBB2, CISD3, CRKRS, TCAP, STARD3, and NEUROD2 were regarded as the hub genes.
ERBB2, generally named Her2, is amplified or overexpressed in 20–30% of invasive breast carcinomas . Moreover, amplification and overexpression of Her2 gene has also been detected in ovarian and gastric cancer [8–10]. Her2 integrates firmly to other epidermal growth factor receptor family members to assemble a heterodimer, which reinforce kinase-mediated activation of downstream signaling pathways, such as PI3K/AKT activation and RET signaling, so as to facilitate the increment and metastasis of cancer cells . As a cell surface related protein, the most critical treatment for Her2 -positive cancer is anti-Her2 strategy, but the subsequent Her2 resistance is a new clinical puzzler . Now, an increasing number of teams have found that many oncogenes co-amplify with the Her2 gene.
PGAP3, CRKRS, STARD3 and NEUROD2 were co-amplified with the Her2 gene. PGAP3, glycosylated phosphatidylinositol (GPI)-specific phospholipase members, is principally involved in the protein distribution and pack . This group confirmed that concurrent amplification of copy number variation at PGAP3 and Her2 loci were detected in BC tissues . Since Her2 gene is significantly associated with the occurrence and invasion of BC, the amplification of PGAP3 gene may affect the effect of Her2 gene on BC. CRKRS, cyclin-dependent kinase 12, also known as CDK12, which phosphorylates RNA polymerase II and modulates transcription factors . Recent studies confirmed that genomic stability needs to be maintained by Cdk12 regulating DNA repair genes by suppressing intron polygadenylation [16–18]. This group study found that CRKRS could induce drug resistance in breast cancer endocrine therapy, which was related to its silent activation of mitogen-activated protein kinase signaling pathway, leading to the loss of estrogen receptor dependence . In breast cancers, CDK12, as a carcinogene, is constantly co-amplified with the ERBB2 oncogene, which suggests that the tumor is prone to invasion and metastasis and poor prognosis [20, 21]. This group study found that CDK12 can not only regulate RNA processing and DNA repair, but also the overexpression of CDK12 can enhancement the oncogenicity of BC cells . STARD3-related protein located on the cell membrane of late endosomes may be involved in fostering the carriage or assignment of cholesterol and sphingolipid to the intracellular membrane compartments and the catabolism of steroid hormones [23, 24]. Recent publication confirmed that the expression level of STARD3 protein is forcefully associated with Her2 amplification, and the high expression of STARD3 may boost BC invasion by increasing membrane cholesterol and intensifying oncogene signal . NEUROD2-related protein is part of the family of neurogenic basic helix-loop-helix proteins, which affect the adjust and control of glutamate and GABA genes . Miangela's research discovered that the copy number of Her2 and NEUROD2 increased in male BC tissue, and merely NEUROD2 amplification appear to have an independent prognostic effect .
PPP1R1B and TCAP are related to anti-Her2 resistance and treatment. PPP1R1B encodes multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp . Recent publications suggested that the protein encoded by PPP1R1B was overexpressed in BC, esophagus cancer, lung cancer, et al [29, 30]. Professional team proved that the resistance of trastuzumab, a key drug in anti-Her2 therapy, was related to the regulation of IGF-1R and AKT signal pathways by t-Darpp [31, 32]. The protein encoded by TCAP gene, widely distributed in cardiomyocytes, is mainly involved in cardiac conduction and striated muscle contraction . Although doxorubicin and anti-Her2 targeting therapy, trastuzumab, are conventional drugs for Her2 + BC, their cardiotoxicity is a thorny clinical issue. The results of Daniel’s study suggest that the variation of TCAP gene may have modifying effects in cardiomyopathy , so whether targeting this gene can shorten the cardiac toxic and side effects of chemotherapy patients.
CISD3, a member of the CDGSH domain-containing family, codes mitochondrial inner NEET protein (MiNT) . Details about biological characteristics of MiNT are relatively indigent, but its high expression in many cancers indicates that it plays a unique role in cancer .
The protein levels PGAP3, PPP1R1B, PNMT, ERBB2, CISD3, CRKRS, TCAP, and STARD3 in tumor tissues were different from normal tissues. And survival analysis shows that PGAP3, PNMT, ERBB2, TCAP, and STARD3 were negatively associated with the overall survival. These results indicate that these genes may be tumorigenic genes in BC.