Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP)
Abstract Introduction Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic brea...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-018-1088-6 |
| _version_ | 1818453535934644224 |
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| author | Camille Lehuédé Xia Li Stéphanie Dauvillier Charlotte Vaysse Camille Franchet Emily Clement David Esteve Mélanie Longué Léonor Chaltiel Sophie Le Gonidec Ikrame Lazar Aline Geneste Charles Dumontet Philippe Valet Laurence Nieto Frédérique Fallone Catherine Muller |
| author_facet | Camille Lehuédé Xia Li Stéphanie Dauvillier Charlotte Vaysse Camille Franchet Emily Clement David Esteve Mélanie Longué Léonor Chaltiel Sophie Le Gonidec Ikrame Lazar Aline Geneste Charles Dumontet Philippe Valet Laurence Nieto Frédérique Fallone Catherine Muller |
| author_sort | Camille Lehuédé |
| collection | DOAJ |
| description | Abstract Introduction Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. Methods We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. Results Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. Conclusions Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance. |
| first_indexed | 2024-12-14T21:40:32Z |
| format | Article |
| id | doaj.art-336d3ced72934ef0a35a1856085c2a3e |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-14T21:40:32Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-336d3ced72934ef0a35a1856085c2a3e2022-12-21T22:46:28ZengBMCBreast Cancer Research1465-542X2019-01-0121111710.1186/s13058-018-1088-6Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP)Camille Lehuédé0Xia Li1Stéphanie Dauvillier2Charlotte Vaysse3Camille Franchet4Emily Clement5David Esteve6Mélanie Longué7Léonor Chaltiel8Sophie Le Gonidec9Ikrame Lazar10Aline Geneste11Charles Dumontet12Philippe Valet13Laurence Nieto14Frédérique Fallone15Catherine Muller16Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Service d’Anatomo-Pathologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-OncopoleInstitut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Département de Biostatistiques, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-OncopoleDépartement de Biostatistiques, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-OncopoleInstitut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPSInstitut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052/CNRSCentre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052/CNRSInstitut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPSInstitut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089Abstract Introduction Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. Methods We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. Results Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. Conclusions Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.http://link.springer.com/article/10.1186/s13058-018-1088-6AdipocytesBreast cancerObesityDoxorubicinMultidrug resistanceMammary adipose tissue |
| spellingShingle | Camille Lehuédé Xia Li Stéphanie Dauvillier Charlotte Vaysse Camille Franchet Emily Clement David Esteve Mélanie Longué Léonor Chaltiel Sophie Le Gonidec Ikrame Lazar Aline Geneste Charles Dumontet Philippe Valet Laurence Nieto Frédérique Fallone Catherine Muller Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) Breast Cancer Research Adipocytes Breast cancer Obesity Doxorubicin Multidrug resistance Mammary adipose tissue |
| title | Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) |
| title_full | Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) |
| title_fullStr | Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) |
| title_full_unstemmed | Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) |
| title_short | Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP) |
| title_sort | adipocytes promote breast cancer resistance to chemotherapy a process amplified by obesity role of the major vault protein mvp |
| topic | Adipocytes Breast cancer Obesity Doxorubicin Multidrug resistance Mammary adipose tissue |
| url | http://link.springer.com/article/10.1186/s13058-018-1088-6 |
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