PTEN is the first reported tumor suppressor gene with phosphatase activity, which plays a vital role in the cell apoptosis, cell cycle arrest and cell migration.[33, 34]. Therefore, PTEN gene plays an important role in the mechanism of multi-drug resistance in cancers. Previous studies have shown that PTEN rs701848 polymorphism might be a candidate pharmacogenomic factor to assess the susceptibility of breast cancer and response and prognosis prediction for chemotherapy in breast cancer . Therefore, it was shown that PTEN gene polymorphism was related to chemotherapy resistance of breast cancer. In recent years, it had been found that PTEN gene polymorphism and chemotherapy resistance are different in breast cancer. However, the potential association between rs786204926 and chemotherapy resistance in breast cancer has not been reported. In our research, we selected PTEN gene polymorphism rs786204926 to study the potential association between PTEN gene polymorphism and chemotherapy resistance in breast cancer. Our research showed that rs786204926 polymorphism was closely related to breast cancer chemotherapy resistance, and found that the AG Heterozygote rs786204926 mutation has decreased risk of breast cancer resistance to anthracycline-based chemotherapy drugs compared with AA/GG individuals. G allele in patients with chemotherapy reduces the risk of drug resistance. Previous studies have confirmed that the association between genetic polymorphisms and breast cancer varies greatly among different races, indicating that different genetic backgrounds have different mutation frequencies. In addition, studies have shown that genetic SNP might change the response to drugs, and there are significant differences between different races. This indicates that mutations have different therapeutic effects on people with different genetic backgrounds. China has a vast territory and a large population. Different regions have different eating habits, cultural backgrounds, living environments, and genetic backgrounds. Our samples mainly collected patients from Northwest China. This study is the first time to detect and analyse the PTEN gene polymorphism of rs786204926 in Northwest China, and provide important theoretical data for establishing a database of PTEN gene polymorphism in Northwest China and promoting pharmacogenomics research to achieve personalized medicine.
Compared with previous studies related to chemotherapy resistance, our research not only analysed gene polymorphism, but also used software to predict the correlation between rs786204926 and AS. Up to 50% of all mutations leading to genetic diseases result in abnormal splicing. It has been found that PTEN splicing aberrations might be caused by genetic mutations at the junction of the splicing sites and deep in the introns. The function of splice sites is to “signal” the assembling snRNAs and auxiliary splicing factors to recognize the “staging area” in order to initiate the assembly of the spliceosome eventually leading to the excision of intron and joining of exons to yield a mature mRNA. This is one of the important mechanisms of alternative splicing involved in the occurrence and development of various diseases. Preliminary studies showed that the impact of genetic polymorphism mutations had been analysed through silicon prediction tools[42, 43]. Therefore, we used silicon analysis to predict the rs786204926 polymorphism to generate new splice sites. The bioinformatics software predicted that rs786204926 is a potential splice acceptor site. When an A > G mutation occurs at this site, it will destroy the wild-type acceptor site to create a new acceptor site and affect alternative splicing. After mutation, there are 18 bases from Pre-mRNA intron 4 will be retained on the mature mRNA, and the exon splicing enhancer (ESE) binding ability will also change, which might eventually cause the mutant protein to have 6 amino acids more than the wild type. In the structure of PTEN protein, the N-terminal phosphatase domain composed of N-terminal amino acids 1-185 is closely related to its phosphatase function. The 6 amino acids produced by the mutant are exactly in this domain, which will cause the protein structure to change. Amino acids 123–130 (HCxxGxxR) are the core sequence of its phosphatase. After mutation, we found that there are varying degrees of protein flexibility changes in these amino acids, especially the decrease of protein flexibility in the core sequence. Flexibility is necessary for a protein to perform its biological function[45, 46]. If the flexibility is reduced, the conformational state of the protein will change greatly, leading to the reduction or even loss of its phosphatase function. PTEN is a tumor suppressor gene with phosphatase activity. On the cell membrane, PTEN mediates the conversion of 3,4,5-phosphatidylinositol triphosphate (PIP3) to PIP2, and inhibits the PI3K/Akt pathway to arrest the cell cycle In the G1 phase[47–49]. When rs786204926A > G is mutated, it might cause changes in mRNA and protein through alternative splicing, and ultimately lead to the reduction or loss of PTEN phosphatase function. Loss of PTEN function will lose its negative regulatory effect on PI3K/Akt, Akt will be continuously activated, the cell cycle will be accelerated, and cell growth and proliferation will be accelerated, reducing the risk of breast cancer chemotherapy resistance. Therefore, we suspect that the chemotherapy resistance of breast cancer patients is mainly caused by the AS of the PTEN gene rs786204926 polymorphism.
Previous studies mainly collected clinical information and blood samples, test results, and statistical analysis to obtain the association between gene polymorphism and breast cancer chemotherapy resistance. However, the mechanism of chemotherapy resistance has not been further studied. In the current research, we have not only conducted association studies, but also predicted the function of SNPs in chemotherapy resistance-related genes by silico analysis. It is predicted that rs786204926 might affect the alternative splicing of PTEN gene (Fig. 5). Although this study has conducted in-depth studies on the potential molecular mechanisms of PTEN gene polymorphism and breast cancer chemotherapy resistance, its limitations should be recognized. The above prediction results require specific experiments to support our findings.