Prognostic significance of altered expression of the members of PI3K/PTEN/AKT/MTOR pathway and PD-L1, AR and EGFR transmembrane proteins in TNBC patients

Breast cancer is the most frequent type of cancer and the leading cause of cancer related death in women. The most aggressive breast cancer subtype is Triple-Negative Breast Cancer (TNBC). It is associated with high recurrence rates, high incidence of distant metastases and poor overall survival. TNBC has a higher mitotic index than hormone receptor-positive (HR+) BC implying strong upregulation of growth factor signaling. We hypothesized that the activation of PI3K/PTEN/AKT/mTOR (PPAM) pathway might be a driving force behind TNBC aggressive phenotype, followed by the alterations of some important transmembrane proteins like PD-L1 (Programmed Death-Ligand 1), EGFR (Epidermal Growth Factor Receptor) and Androgen Receptor (AR). To that end we analyzed immunoexpression of these genes in 125 postoperative samples of TNBC patients and correlated obtained results with clinicopathological parameters and survival. Our results imply that these genes should be considered as packages of genes and should be analyzed simultaneously, not individually. Namely, loss of PTEN (low expression) and high expressions of PI3K and mTOR are associated with lymphatic node metastases, advanced pathological prognostic stage, larger tumor size and with poor outcome of TNBC patients. Therefore, we think that PTEN-reduced/PI3Khigh/mTOR-high immunoexpression is a high-risk profile for TNBC patients. Further, our result showed that PD-L1 low/AR low/EGFR high immunoexpression, with the support of Ki67 expression, is a real “high risk” profile for these patients. We believe that these two packages could be a promising formula for better prediction and exploration of better treatment modalities for TNBC patients.