Clinicopathological Characteristics And Prognostic Significance Of PI3K-Akt-mTOR Signaling Pathway In Breast Cancer

Breast cancer(BC)has become the most common malignant tumor for women all over the world,showing an increasing morbidity year by year.With the development of molecular biological technique,BC could be further divided into four subtypes:Luminal A,Luminal B,human epithelial growth factor receptor 2(HER2)overexpression and triple negative breast cancer(TNBC).There are obvious differences among different subtypes of BC with regard to the gene expression profiles,the expression of molecular markers and prognosis.Particularly,TNBC which is still a study challenge at present demonstrates the features of high heterogeneity,strong invasion,poor biological behavior and deficiency of effective targets.The development of BC involves the activation of oncogenes and inactivation of suppressor genes which will result in obstruction of protein synthesis.Then,abnormity in multiple signaling pathways induces the change of cellular biological behaviors and the formation of tumors.PI3K-Akt-mTOR is a complicated and important intracellular pathway.The aberrant activation of the signaling is associated with the development of BC,and the inhibition on the signaling also has significance for the treatment of BC.PIK3CA mutations and p-mTOR expression are two critical regulators for activating the pathway.The expression level and functional mechanism of the two markers exist differences among various BC subtypes.Specifically,few research have discussed the role of PI3K pathway on TNBC and the conclusions remain controversy.On the one hand,immunohistochemistry(IHC)were used to stain with p-mTOR and direct sequencing was applied to detect the mutations of PIK3CA gene in order to identify the role of the pathway in TNBC.On the other hand,we also assessed the expression of p-mTOR and its prognostic value in Luminal A and Luminal B subtypes in order to have a better understanding of the protein staining in different BC subtypes.The contents of this study are divided into two sections as followed:Section 1:Direct sequencing was applied to detect the mutations of PIK3CA gene and IHC method was used to assess downstream effector p-mTOR expression in a total of 218 TNBC patients.We systematically evaluated the associations of these two biomarkers and clinicopathological characteristics and outcomes in TNBC.We classified TNBC into 134(61.5%)cases of basal-like breast cancer(BLBC)and 84(38.5%)cases of non-basal-like breast cancer(non-BLBC)based on IHC staining for EGFR and CK5/6.Mutations were identified in 25(11.5%)cases which were related to basal-like subtype.As for p-mTOR expression,47.7%of the tumors were positive and the staining was shown in cytoplasm,nuclear and cytomembrane.There were significant differences observed in tumor size,lymph node status,clinical stage and PIK3CA mutant between p-mTOR positive and p-mTOR negative cases.Furthermore,patients with nuclear staining of p-mTOR have higher levels of lymph node metastasis and tumor embolus than negative group.Multivariate analyses further demonstrated that PIK3CA mutations,p-mTOR expression and lymph node metastasis were independently associated with worse overall survival.Further research based on this study are expected to provide theoretical reference for targeted therapy and prognosis evaluation for TNBC patients.Section 2:To explore the difference of p-mTOR expression level in 75 of Luminal A cases and 136 of Luminal B cases,and comprehensively and systematically analyze the correlations of the protein expression with clinical pathological features as well as prognosis.The staining of p-mTOR was shown in cytoplasm,nuclear and cytomembrane.p-mTOR was positive in 75(50.7%)Luminal A subtype.The cytoplasmic positive group was correlated with early stage and the cytomembrane staining group was related to age less than 50.Furthermore,patients with p-mTOR total staining group demonstrated longer disease-free survival time by Kaplan-Meier analysis.In Luminal B subtype,89(65.4%)patients were found to have positive p-mTOR.The cytomembrane positive group was associated with advanced-stage.Patients with cytomembrane staining pattern were tend to have an unfavorable disease-free survival time by Kaplan-Meier analysis.In a multivariable analysis,the cytomembrane positive group was independently associated with worse disease-free survival.