PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway

Abstract

Background: Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. PIK3CA is an oncogene that encodes the p110α subunit of class IA PI3K to regulate cell proliferation and apoptosis. Some reports have observed neoadjuvant chemotherapy (NAC) to have poor pathological complete response (pCR) rates in TNBC with PIK3CA mutation. This study aimed to explore the mechanism of how mutant PIK3CA alters chemotherapeutic susceptibility in TNBC. Methods: TNBC cell lines (MDA-MB-231 and MDA-MB-468) with PIK3CA gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for in vivo experiments. Epirubicin was used as the chemotherapeutic agent. Cell viability, cell cycle, apoptosis, and Transwell assays were conducted for phenotype analysis. Western blot, quantitative reverse transcriptionpolymerase chain reaction, and immunohistochemistry were used to detect gene and protein expression levels. A clinical analysis of 50 patients with TNBC was also performed.Results: Cell viability and Transwell assays showed that PIK3CA mutation promoted TNBC cell growth and conferred an enhanced migratory phenotype. Cell cycle and apoptosis assays showed that PIK3CA mutation moderately improved the proliferation ability of TNBC cells and remarkably inhibited their apoptosis. After epirubicin therapy, the proportion of early apoptotic cells decreased among cells with PIK3CA mutation. Further, xenograft tumors grew faster in NOD/SCID mice injected with mutated cell lines than in control group, suggesting that PIK3CA mutation caused chemotherapy resistance. Importantly, western blot and immunohistochemical analysis showed that cells and mouse tumors in the PIK3CA mutation groups exhibited different expression levels of apoptosis-related markers (Xiap, Bcl-2, and Caspase 3) and proteins associated with the PI3K/AKT/mTOR pathway (p110α, AKT, p-AKT, mTOR, p-mTOR, p-4E-BP1, p-p70S6K, and Pten). Moreover, prognostic analysis of 50 patients with TNBC indicated that PIK3CA mutation might be linked with relapse and death.Conclusions: PIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…PIK3CA mutations have also been associated with resistance of TNBC cell lines to chemotherapy [ 195 ]. In addition, activating PIK3CA mutations in basal-like breast cancer were found to induce paracrine activation of AREG/EGFR/ERK signaling [ 196 ].…”

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect

“…The phosphatidylinositol-4-5-bisphosphate-3-kinase catalytic subunit-α (PIK3CA) gene was over-expressed in DMBA-administered rats. PIK3CA encodes the p110α subunit of class IA PI3K to phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) and transforms it into phosphoinositide 3,4,5 trisphosphate (PIP3), and subsequently stimulates further downstream pathways that finally leads to advanced cell growth, proliferation and resistance [ 50 , 51 , 52 ]. Activation of oncogenes as PIK3CA and loss of tumor suppressors are thought to be early breast cancer events.…”

Baseline Mutations and Up-Regulation of PI3K-AKT Pathway Serve as Potential Indicators of Lack of Response to Neoadjuvant Chemotherapy in Stage II/III Breast Cancer

“…PIK3CA mutations and AKT activation by phosphorylation (pAKT) are frequently detected in BC, and pAKT regulates growth, proliferation, differentiation, tumorigenesis and other critical cellular activities ( 37 , 38 ). BC tumor cells with PIK3CA mutations had lower probability of early apoptosis after being treated with epirubicin, and abnormal protein expression in PI3K-AKT signaling pathway, suggesting the association between chemotherapy resistance and activated PI3K-AKT pathway in TNBC ( 39 ). In one BC study, mutated PI3K-AKT pathways were detected among 29.8% TNBC patients, and over 70% of these patients carried PIK3CA mutations, which was consistent with our findings in this study including 4 BC subtypes ( 40 ).…”