PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway
Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. is an oncogene that encodes the p110α subunit of class IA PI3K to regulate cell proliferation and apoptosis. Some reports have observed neoadjuvant chemotherapy (...
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Published in | Annals of translational medicine Vol. 9; no. 5; p. 410 |
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Main Authors | , , , , , , , , , , , |
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01.03.2021
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Abstract | Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery.
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.
TNBC cell lines (MDA-MB-231 and MDA-MB-468) with
gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for
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.
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.
PIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway. |
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AbstractList | BACKGROUNDTriple-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. METHODSTNBC 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. RESULTSCell 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. CONCLUSIONSPIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway. Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. 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. TNBC cell lines (MDA-MB-231 and MDA-MB-468) with gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for 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. 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. PIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway. |
Author | Ji, Yashuang Wei, Yufan Zhang, Yanjun Hong, Chenyan Zhong, Yuting Zhu, Junyong Geng, Rui Guan, Qingyu Min, Ningning Qi, Aiying Hu, Huayu Li, Xiru |
Author_xml | – sequence: 1 givenname: Huayu surname: Hu fullname: Hu, Huayu organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 2 givenname: Junyong surname: Zhu fullname: Zhu, Junyong organization: Medical School of Chinese PLA, Beijing, China – sequence: 3 givenname: Yuting surname: Zhong fullname: Zhong, Yuting organization: Medical School of Chinese PLA, Beijing, China – sequence: 4 givenname: Rui surname: Geng fullname: Geng, Rui organization: Medical School of Chinese PLA, Beijing, China – sequence: 5 givenname: Yashuang surname: Ji fullname: Ji, Yashuang organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 6 givenname: Qingyu surname: Guan fullname: Guan, Qingyu organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 7 givenname: Chenyan surname: Hong fullname: Hong, Chenyan organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 8 givenname: Yufan surname: Wei fullname: Wei, Yufan organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 9 givenname: Ningning surname: Min fullname: Min, Ningning organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 10 givenname: Aiying surname: Qi fullname: Qi, Aiying organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 11 givenname: Yanjun surname: Zhang fullname: Zhang, Yanjun organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China – sequence: 12 givenname: Xiru surname: Li fullname: Li, Xiru organization: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, China |
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Keywords | chemotherapy resistance apoptosis Triple-negative breast cancer (TNBC) PI3K/AKT/mTOR pathway PIK3CA mutation |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributions: (I) Conception and design: X Li, Y Zhang, A Qi; (II) Administrative support: X Li; (III) Provision of study materials or patients: X Li; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. |
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Snippet | Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery.
is an oncogene that... BACKGROUNDTriple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. PIK3CA is... |
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Title | PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway |
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