Everolimus Inhibits the Progression of Ductal Carcinoma
| Autor: | Guang, Chen, Xiao-Fei, Ding, Kyle, Pressley, Hakim, Bouamar, Bingzhi, Wang, Guixi, Zheng, Larry E, Broome, Alia, Nazarullah, Andrew J, Brenner, Virginia, Kaklamani, Ismail, Jatoi, Lu-Zhe, Sun |
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| Rok vydání: | 2019 |
| Předmět: |
Receptor
ErbB-2 Down-Regulation Mice Nude Antineoplastic Agents Breast Neoplasms Mice Transgenic Xenograft Model Antitumor Assays Article body regions Mice Carcinoma Intraductal Noninfiltrating Matrix Metalloproteinase 9 Cell Movement Cell Line Tumor Spheroids Cellular Biomarkers Tumor Disease Progression Animals Humans Female Everolimus skin and connective tissue diseases neoplasms |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 |
| Popis: | PURPOSE: We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression. EXPERIMENTAL DESIGN: The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and immunohistochemistry in these models and in DCIS patients before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells. RESULTS: Everolimus significantly inhibited the invasion of human breast cancer cells in vitro. Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the in vitro and in vivo models, and in breast tissues from DCIS patients treated with rapamycin for one week. Moreover, overexpression of MMP9 stimulated the invasion whereas knockdown of MMP9 inhibited the invasion of breast cancer cell-formed spheroids in vitro and DCIS in vivo. Knockdown of MMP9 also nullified the invasion inhibition by everolimus in vitro and in vivo. CONCLUSIONS: Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or Early-Stage IDC therapy. |
| Databáze: | OpenAIRE |
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