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PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway
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 neoadju...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033310/ https://www.ncbi.nlm.nih.gov/pubmed/33842631 http://dx.doi.org/10.21037/atm-21-698 |
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author | Hu, Huayu Zhu, Junyong Zhong, Yuting Geng, Rui Ji, Yashuang Guan, Qingyu Hong, Chenyan Wei, Yufan Min, Ningning Qi, Aiying Zhang, Yanjun Li, Xiru |
author_facet | Hu, Huayu Zhu, Junyong Zhong, Yuting Geng, Rui Ji, Yashuang Guan, Qingyu Hong, Chenyan Wei, Yufan Min, Ningning Qi, Aiying Zhang, Yanjun Li, Xiru |
author_sort | Hu, Huayu |
collection | PubMed |
description | 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 transcription-polymerase 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. |
format | Online Article Text |
id | pubmed-8033310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-80333102021-04-09 PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway Hu, Huayu Zhu, Junyong Zhong, Yuting Geng, Rui Ji, Yashuang Guan, Qingyu Hong, Chenyan Wei, Yufan Min, Ningning Qi, Aiying Zhang, Yanjun Li, Xiru Ann Transl Med Original Article 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 transcription-polymerase 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. AME Publishing Company 2021-03 /pmc/articles/PMC8033310/ /pubmed/33842631 http://dx.doi.org/10.21037/atm-21-698 Text en 2021 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Hu, Huayu Zhu, Junyong Zhong, Yuting Geng, Rui Ji, Yashuang Guan, Qingyu Hong, Chenyan Wei, Yufan Min, Ningning Qi, Aiying Zhang, Yanjun Li, Xiru PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title_full | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title_fullStr | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title_full_unstemmed | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title_short | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
title_sort | pik3ca mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the pi3k/akt/mtor signaling pathway |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033310/ https://www.ncbi.nlm.nih.gov/pubmed/33842631 http://dx.doi.org/10.21037/atm-21-698 |
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