Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis
Mutation or loss of the tumor suppressor gene PTEN or its functional status in tumor stromal cells may affect tumor occurrence, development, invasion, and metastasis, in which, however, the role of overall low PTEN expression, mutation, or deletion in the tumor-bearing host has rarely been reported....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.825484/full |
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| author | Jing Chen Jingjing Sun Qunfeng Wang Yanze Du Jie Cheng Juan Yi Bei Xie Suya Jin Gang Chen Lina Wang Xiaoyuan Wang Hulai Wei |
| author_facet | Jing Chen Jingjing Sun Qunfeng Wang Yanze Du Jie Cheng Juan Yi Bei Xie Suya Jin Gang Chen Lina Wang Xiaoyuan Wang Hulai Wei |
| author_sort | Jing Chen |
| collection | DOAJ |
| description | Mutation or loss of the tumor suppressor gene PTEN or its functional status in tumor stromal cells may affect tumor occurrence, development, invasion, and metastasis, in which, however, the role of overall low PTEN expression, mutation, or deletion in the tumor-bearing host has rarely been reported. Breast cancer is a common highly invasive metastatic tumor. We therefore treated mouse breast cancer 4T1 cells with the specific PTEN inhibitor VO-OHpic to study the effects of PTEN suppression or deletion on malignant behavior in vivo and in vitro. VO-OHpic effectively inhibited PTEN gene/protein expression in 4T1 cells, accelerated cell proliferation, and enhanced cell migration and invasion. We also transplanted 4T1 cells with VO-OHpic-inhibited PTEN into mice to create orthotopic and metastatic breast cancer models. The proliferation of 4T1 cells in mouse mammary gland was increased and distant metastasis was enhanced, with metastatic foci in the lung, liver, and intestinal tract. In addition, injection of mice with VO-OHpic to inhibit PTEN in the overall microenvironment accelerated the proliferation of transplanted 4T1 cells and enhanced distant metastasis and the formation of metastatic tumors. Metastatic foci formed in the lung, liver, intestine, thymus, and brain, and PTEN levels in the organ/tissues were negatively associated with the formation of metastatic foci. Similarly, inoculation of PTEN-deficient 4T1 cells into systemic PTEN-inhibited mice further enhanced the orthotopic growth and distant metastasis of 4T1 breast cancer. VO-OHpic inhibition of PTEN in 4T1 cells was also associated with significantly increased phosphorylation of Akt and phosphoinositide 3-kinase (PI3K), suggesting that inhibition of PTEN could activate the PI3K-Akt pathway, as a key signaling pathway regulating cell proliferation and death. These results confirmed that functional loss or deletion of the tumor suppressor gene PTEN significantly enhanced the proliferation, invasion, and metastasis of 4T1 cells. Systemic decrease or deletion of PTEN in the organism or organ/tissue microenvironment was conducive to the proliferation of breast cancer cells in situ and distant metastasis. These results suggest that, as well the PTEN in cancer cells the systemic microenvironment PTEN intensely mediates the proliferation, invasion and metastasis of mouse breast cancer cells via regulating the PI3K-Akt signaling pathway. |
| first_indexed | 2024-12-20T23:17:25Z |
| format | Article |
| id | doaj.art-1d8321d1d7664c26a412c21d5d2001ec |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-20T23:17:25Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-1d8321d1d7664c26a412c21d5d2001ec2022-12-21T19:23:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.825484825484Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and MetastasisJing Chen0Jingjing Sun1Qunfeng Wang2Yanze Du3Jie Cheng4Juan Yi5Bei Xie6Suya Jin7Gang Chen8Lina Wang9Xiaoyuan Wang10Hulai Wei11Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaDepartment of Clinical Laboratory, The First Hospital of Lanzhou University, Lanzhou, Gansu, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaDepartment of Thoracic Surgery, Gansu Provincial Cancer Hospital, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaMutation or loss of the tumor suppressor gene PTEN or its functional status in tumor stromal cells may affect tumor occurrence, development, invasion, and metastasis, in which, however, the role of overall low PTEN expression, mutation, or deletion in the tumor-bearing host has rarely been reported. Breast cancer is a common highly invasive metastatic tumor. We therefore treated mouse breast cancer 4T1 cells with the specific PTEN inhibitor VO-OHpic to study the effects of PTEN suppression or deletion on malignant behavior in vivo and in vitro. VO-OHpic effectively inhibited PTEN gene/protein expression in 4T1 cells, accelerated cell proliferation, and enhanced cell migration and invasion. We also transplanted 4T1 cells with VO-OHpic-inhibited PTEN into mice to create orthotopic and metastatic breast cancer models. The proliferation of 4T1 cells in mouse mammary gland was increased and distant metastasis was enhanced, with metastatic foci in the lung, liver, and intestinal tract. In addition, injection of mice with VO-OHpic to inhibit PTEN in the overall microenvironment accelerated the proliferation of transplanted 4T1 cells and enhanced distant metastasis and the formation of metastatic tumors. Metastatic foci formed in the lung, liver, intestine, thymus, and brain, and PTEN levels in the organ/tissues were negatively associated with the formation of metastatic foci. Similarly, inoculation of PTEN-deficient 4T1 cells into systemic PTEN-inhibited mice further enhanced the orthotopic growth and distant metastasis of 4T1 breast cancer. VO-OHpic inhibition of PTEN in 4T1 cells was also associated with significantly increased phosphorylation of Akt and phosphoinositide 3-kinase (PI3K), suggesting that inhibition of PTEN could activate the PI3K-Akt pathway, as a key signaling pathway regulating cell proliferation and death. These results confirmed that functional loss or deletion of the tumor suppressor gene PTEN significantly enhanced the proliferation, invasion, and metastasis of 4T1 cells. Systemic decrease or deletion of PTEN in the organism or organ/tissue microenvironment was conducive to the proliferation of breast cancer cells in situ and distant metastasis. These results suggest that, as well the PTEN in cancer cells the systemic microenvironment PTEN intensely mediates the proliferation, invasion and metastasis of mouse breast cancer cells via regulating the PI3K-Akt signaling pathway.https://www.frontiersin.org/articles/10.3389/fonc.2022.825484/fullPTEN4T1 cellmultiplicationinvasionmetastasis |
| spellingShingle | Jing Chen Jingjing Sun Qunfeng Wang Yanze Du Jie Cheng Juan Yi Bei Xie Suya Jin Gang Chen Lina Wang Xiaoyuan Wang Hulai Wei Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis Frontiers in Oncology PTEN 4T1 cell multiplication invasion metastasis |
| title | Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis |
| title_full | Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis |
| title_fullStr | Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis |
| title_full_unstemmed | Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis |
| title_short | Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis |
| title_sort | systemic deficiency of pten accelerates breast cancer growth and metastasis |
| topic | PTEN 4T1 cell multiplication invasion metastasis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.825484/full |
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