Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer

Abstract

Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a ‘high risk’ profile of TNBC.

Inhibition of NF-kB and COX-2 by andrographolide regulates the progression of cervical cancer by promoting PTEN expression and suppressing PI3K/AKT signalling pathway

“…PTEN acts as a checkpoint for PI3K, which enhances the PI3K/AKT survival pathway. PTEN deficiency and high PI3K and mTOR expression are linked to a poor prognosis in triple negative breast cancer patients 60 . In our study the loss of PTEN immunoreactivity and upregulation of PI3K were noted in cervical cancer patients.…”

Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines

“…PI3K is highly expressed in 40% of TNBC, and its expression is marginally higher in TNBC than in hormone receptor-expressing (HR+) breast cancer [ 37 ]. A high expression of PI3K is correlated with a larger tumor size, lymph node metastases, advanced tumor stage in TNBC [ 37 ], and unfavorable outcomes in various solid tumors [ 38 , 39 , 40 , 41 ]. The PI3K/mTOR pathway is also strongly activated in IBC tumors [ 42 ], and the PI3K/Akt and PI3K/mTOR pathways are crucial for IBC invasion [ 43 , 44 ].…”

“…mTOR is a key integrator of signals that control protein and lipid biosynthesis and growth factor–driven cell cycle progression [ 57 ]. mTOR was highly expressed in 44% of TNBC, and the high expression of mTOR was correlated with a high pathological prognostic TNBC stage [ 37 ]. Expression levels of mTOR were significantly higher in TNBC than in HR+ tumors, and high mTOR expression was associated with advanced tumor stage [ 37 ].…”

“…mTOR was highly expressed in 44% of TNBC, and the high expression of mTOR was correlated with a high pathological prognostic TNBC stage [ 37 ]. Expression levels of mTOR were significantly higher in TNBC than in HR+ tumors, and high mTOR expression was associated with advanced tumor stage [ 37 ]. Everolimus, a derivative of rapamycin (sirolimus), inhibits mTOR activity by binding to its intracellular receptor FKBP12 to prevent the downstream signaling required for cell cycle progression and cell proliferation [ 58 ].…”

Bioinformatic miRNA-mRNAs Analysis Revels to miR-934 as a Potential Regulator of the Epithelial–Mesenchymal Transition in Triple-Negative Breast Cancer

“…The homologous tumor suppressor of phosphatase and tensin (PTEN) downregulation is common in TNBC. Accordingly, previous investigations have reported a relationship between PTEN expression and the EMT process [ 10 , 11 , 12 , 13 ]. In contrast, some studies have suggested that, in different cancer types, early growth response 2 (EGR2) expression is correlated with apoptosis promotion, with the ETM process inhibitor playing a role in this correlation.…”