An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway
In clinical practice, some breast cancer (BC) patients carry a rare ERBB2 in-frame insertion (p. Pro780_Tyr781insGlySerPro) and are resistant to anti-ERBB2 therapy. To explore the potential procarcinogenic role of this ERBB2 mutation, we conducted the present study using BC cells overexpressing wild...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2020-01-01
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| Series: | Biology Open |
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| Online Access: | http://bio.biologists.org/content/9/1/bio047662 |
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| author | Zi-Yan Yang Liu Yang Chun-Wei Xu Xiao-Jia Wang Lei Lei |
| author_facet | Zi-Yan Yang Liu Yang Chun-Wei Xu Xiao-Jia Wang Lei Lei |
| author_sort | Zi-Yan Yang |
| collection | DOAJ |
| description | In clinical practice, some breast cancer (BC) patients carry a rare ERBB2 in-frame insertion (p. Pro780_Tyr781insGlySerPro) and are resistant to anti-ERBB2 therapy. To explore the potential procarcinogenic role of this ERBB2 mutation, we conducted the present study using BC cells overexpressing wild-type (WT) ERBB2 or P780-Y781 ERBB2 [mutated (MT)]. MDA-MB-231 and MCF-7 cells were transfected with the following plasmids using a lentivirus system: negative control (ERBB2-NC), WT ERBB2 overexpression (ERBB2-WT), and P780-Y781 ERBB2 overexpression (ERBB2-MT). P780-Y781 ERBB2 conferred significant resistance to lapatinib, as assessed by cell viability and colony counts. Analysis of the cell cycle showed that the P780-Y781 ERBB2 group showed an elevated proportion of cells in S, G2, and M phases compared with WT ERBB2 when exposed to lapatinib. Following lapatinib treatment, phosphorylated AKT (p-AKT) was strongly upregulated in the P780-Y781 ERBB2 group. Among ERBB2+ patients, the P780-Y781 ERBB2 group showed increased levels of p-AKT. Furthermore, the AKT inhibitor perifosine effectively suppressed lapatinib resistance, as indicated by the lapatinib inhibition curve and results of the colony formation assay, and decreased AKT phosphorylation. Altogether, we discovered a procarcinogenic mutation of ERBB2 that enhances BC cell growth through AKT signaling and causes resistance to lapatinib. Patients with this in-frame insertion mutation of ERBB2 should be recommended other therapeutic strategies apart from ERBB2 tyrosine kinase inhibitors, in particular lapatinib. |
| first_indexed | 2024-12-19T09:17:12Z |
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| id | doaj.art-edffa9dcdd6e42f7b921f52a3d30fccf |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-19T09:17:12Z |
| publishDate | 2020-01-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-edffa9dcdd6e42f7b921f52a3d30fccf2022-12-21T20:28:05ZengThe Company of BiologistsBiology Open2046-63902020-01-019110.1242/bio.047662047662An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathwayZi-Yan Yang0Liu Yang1Chun-Wei Xu2Xiao-Jia Wang3Lei Lei4 The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310022, China Shanghai Dunlu Biomedical Technology Co. Ltd. Shanghai 201611, China Department of Pathology, Fujian Cancer Hospital, Fujian Medical University. No. 420, Fuma Road, Fuzhou, Fujian 350014, China Department of Chemotherapy, Zhejiang Cancer Hospital. No.1 Banshan East Street, Gongshu District, Hangzhou, Zhejiang 310022, China Department of Chemotherapy, Zhejiang Cancer Hospital. No.1 Banshan East Street, Gongshu District, Hangzhou, Zhejiang 310022, China In clinical practice, some breast cancer (BC) patients carry a rare ERBB2 in-frame insertion (p. Pro780_Tyr781insGlySerPro) and are resistant to anti-ERBB2 therapy. To explore the potential procarcinogenic role of this ERBB2 mutation, we conducted the present study using BC cells overexpressing wild-type (WT) ERBB2 or P780-Y781 ERBB2 [mutated (MT)]. MDA-MB-231 and MCF-7 cells were transfected with the following plasmids using a lentivirus system: negative control (ERBB2-NC), WT ERBB2 overexpression (ERBB2-WT), and P780-Y781 ERBB2 overexpression (ERBB2-MT). P780-Y781 ERBB2 conferred significant resistance to lapatinib, as assessed by cell viability and colony counts. Analysis of the cell cycle showed that the P780-Y781 ERBB2 group showed an elevated proportion of cells in S, G2, and M phases compared with WT ERBB2 when exposed to lapatinib. Following lapatinib treatment, phosphorylated AKT (p-AKT) was strongly upregulated in the P780-Y781 ERBB2 group. Among ERBB2+ patients, the P780-Y781 ERBB2 group showed increased levels of p-AKT. Furthermore, the AKT inhibitor perifosine effectively suppressed lapatinib resistance, as indicated by the lapatinib inhibition curve and results of the colony formation assay, and decreased AKT phosphorylation. Altogether, we discovered a procarcinogenic mutation of ERBB2 that enhances BC cell growth through AKT signaling and causes resistance to lapatinib. Patients with this in-frame insertion mutation of ERBB2 should be recommended other therapeutic strategies apart from ERBB2 tyrosine kinase inhibitors, in particular lapatinib.http://bio.biologists.org/content/9/1/bio047662breast cancererbb2insertion mutationlapatinibakt |
| spellingShingle | Zi-Yan Yang Liu Yang Chun-Wei Xu Xiao-Jia Wang Lei Lei An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway Biology Open breast cancer erbb2 insertion mutation lapatinib akt |
| title | An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway |
| title_full | An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway |
| title_fullStr | An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway |
| title_full_unstemmed | An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway |
| title_short | An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway |
| title_sort | insertion mutation of erbb2 enhances breast cancer cell growth and confers resistance to lapatinib through akt signaling pathway |
| topic | breast cancer erbb2 insertion mutation lapatinib akt |
| url | http://bio.biologists.org/content/9/1/bio047662 |
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