Precision medicine (PM) is a disease treatment and prevention strategy that considers individual differences in genes, environment, and lifestyle22. Compared with stratified medicine (SM), which includes a population-indicating drug changed according to a specific molecule, PM is designed to indicate treatment individually23. However, current opinions and technical limitations are not entirely correct or precise. PM is still an indispensable way to reduce cancer treatment’s toxicity and increase its benefit to patients24.
Lung cancer, colon cancer, and breast cancer are the three most common cancers in the world25,26. Women diagnosed with breast cancer have a 5-year survival rate of 89%, a 10-year survival rate of 83%, and a 15-year survival rate of 78%. Although improvements have been made in early diagnosis, new targets against BRCA still cannot satisfy clinical requirements. Studies have shown that each type of breast cancer has a high level of heterogeneity. It is composed of several molecular subgroups driven by different molecular subgroups, indicating that it can be treated according to the individual molecular conditions of the tumor27.
A large amount of data shows that claudins are abnormally expressed in a variety of cancers, so the role of claudins in carcinogenesis and progression to metastasis has become a hot area28. The CLDN expression changes observed in normal and cancerous tissues are cancer-specific. For example, CLDN3 is up-regulated in prostate cancer, ovarian cancer, and breast cancer29–31. CLDN7 is low expressed in head and neck tumors and breast cancer, but highly expressed in cervical cancer and ovarian cancer32–34. CLDN1 is lost in glioblastoma multiforme and Melanoma, while it is overexpressed in colon cancer and cervical cancer33,35−37. CLDN10 is increased in both thyroid cancer and hepatocellular carcinoma38,39. CLDN4 is sometimes increased and sometimes decreased in breast and gastric cancer, while it is always highly expressed in prostate cancer and ovarian cancer29–31,40−42. Although the functional role of CLDN11 in cancer is still unclear, the differential expression between tumor and normal cells, and the location of the membrane makes it a significant candidate for cancer treatment43.
To further study the role of CLDN11 in IDC and ILC patients, we performed the expression, correlation, and survival analysis of CLDN11 in IDC and ILC patients. Microarray expression analysis revealed that the mRNA level of CLDN11 down-regulated in patients with IDC and ILC. CLDN11 is negatively correlated with pro-oncogene IKBKE expression and positively correlated with tumor suppressor EST1 expression in IDC and ILC samples. Meanwhile, higher expression of CLDN11 indicated a more prolonged overall survival and disease-free survival time than the lower groups, which suggested CLDN11 as a tumor suppressor gene in this disease.
Clinical variables, including age, stage, subtype, and gene mutation status, may predict cancers’ development. To better understand how these factors influenced breast cancer patient progression, the CLDN11 level was classified into high and low expression groups according to the average value for OS and DFS analysis. Increasing the CLDN11 level has a better prognosis for patients both over and under 60-year-old, and those over 60-year-old are statistically significant. As for the stage, higher expression of CLDN11 level has a higher overall survival in the early stage(Ⅰ-Ⅱ) and the advanced stage(Ⅲ-Ⅳ). There is no statistically significant, but the trend is evident. We also find that the wild type status of TP53 and the mutation status of PIK3CA showed better OS when the CLDN11 expression level was high. Also, regardless of the high or low expression of CLDN11, there is no significant effect on the OS and DFS of different subtypes of IDC and ILC. In general, age, TNM stage, and gene mutation are all related factors for IDC and ILC, except to subtypes. These suggest that the targeted therapy of CLDN11 may have good significance for age, TNM staging, wild-type TP53, and mutant PIK3CA.
IKBKE, a nonclassical IKK family member, plays an essential role in regulating inflammation, activating and increasing immune cells, and metabolic diseases44. Studies have shown that IKBKE plays a carcinogenic effect in pancreatic cancer induced by KRAS45. Besides, compared with normal hematopoietic cells, the expression level of IKBKE in myeloid leukemia cells is higher. Inhibition of IKBKE can reduce the viability of AML cells46. Jie Lu et al. found that IKBKE increased the two crucial downstream factors of the hippo pathway and induce epithelial-mesenchymal transition (EMT), ultimately leading to tumor invasion and metastasis47. Boehm and colleagues indicate that IKBKE is amplified and overexpressed in a considerable number of breast cancer cell lines and primary breast tumors, so IKBKE is described as an oncogene of breast cancer11. ETS1 is defined as an oncogene because it contributes to tumor angiogenesis and invasiveness in cancer strongly expressed in vascular endothelial cells and the adjacent interstitial cells48,49. ETS1 promotes the metastasis of non-small cell lung cancer (NSCLC) and is associated with poor prognosis50. ETS-1 regulates intracellular glutathione levels and promoting the development of ovarian cancer51. In melanoma, the upregulation of ETS1 contributes to the malignant phenotype16. Besides, studies shown that ETS1 is involved in the invasion and metastasis of colon cancer. In human breast cancer, overexpression of ETS-1 has been found to a strong independent relationship with the poor prognosis of breast cancer, which may be related to epithelial-to-mesenchymal transition (EMT)52,53.
There are several genes known to be associated with the prognosis of invasive breast cancer. The TP53 gene, which is the most frequently mutated gene in human cancer, called ‘the guardian of the genome’54. It has been found playing an essential role in inhibiting the progression of bone and soft tissue sarcoma55. Mutations of TP53 in the direct DNA contact area lead to accelerated tumor progression of head and neck squamous cell carcinoma and reduced response to treatment56,57. In multiple bone marrow, changes in the tumor suppressor gene TP53 are associated with poor prognosis58. TP53 is the most frequently mutated gene in invasive breast cancer, the survival rate of patients with TP53 mutations is significantly reduced59. TP53 has different roles in different subtypes, among the most prevalent breast cancer subtypes, the frequency of TP53 mutation is the lowest in luminal A, while the basal-like subtype is the highest60. Besides, TP53 is also mutated in most TN breast cancers20.
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are crucial lipid kinases in neoplasia61. PIK3CA, which encodes the p110αcatalytic subunit of PI3K, has been found to be mutated in a variety of tumors, and may act as an oncogene in human cancers62,63. Pearson and colleagues showed that PIK3CA mutation correlates with low-grade prostate cancer patient survival64. In gastric cancer, the prevalence of somatic mutations in PIK3CA is relatively high, and its mutations cluster within the MSI (microsatellite unstable tumors) subset of gastric tumors, supporting PIK3CA as the main oncogene in gastric cancer65,66. Studies have also indicated that PIK3CA mutation is related to the poor survival rate in resectable stage I to III colon cancer, providing a new research direction for the treatment of colon cancer67. In addition, it has found that PIK3CA mutations occur with high frequency in breast cancer68. And targeted inhibitors of PI3K/Akt/mTOR pathway can inhibit brain metastasis of PIK3CA-mutant breast cancer69. In our study, we found that mutate PIK3CA and the wild type of TP53 are significantly correlated with the OS of invasive breast cancer, and the high expression of CLDN11 is associated with a better survival time, which may provide new ideas for targeted drug research.
In conclusion, CLDN11 acted as a tumor suppressor gene in IDC and ILC patients, and downregulation of the CLDN11 gene is related to the poor prognosis in IDC and ILC patients. Besides, age, TNM stage, and gene mutation are stratification factors of CLDN11 in IDC and ILC. Therefore, the determination of CLDN11 gene expression may be useful for predicting prognosis and provide significant implications for novel treatment strategy based on precision medicine in IDC and ILC.