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- W1547094328 abstract "HER2 is overexpressed in 20-25% invasive breast tumors, and correlates with low free disease survival. Trastuzumab (Tz), monoclonal antibody anti HER2, is used to treat HER2+ tumors; however more than half of them are resistant or acquire resistance during treatment. Autophagy has been proposed as a tumoral escape mechanism. Multicellular tumor spheroids (MCS) are a model of cell growth in 3D that mimics the structure of in vivo avascular tumors. We have previously demonstrated that MCS present different subpopulations, with a gradient of proliferative, quiescent and apoptotic cells towards the center of the spheroid and these characteristics makes it more resistant to Tz than monolayers. The aim of this study was to analyze the role of autophagy in MCS growth and its relevance on the resistance of breast cancer cells to Tz. MCS of overexpressing HER2+ human mammary tumor cells (BT474 cell line) were cultured as cell suspensions on agar, one per well, and experiments were conducted when MCS reached 550 um initial size. When the autophagy marker LC3 was analyzed in MCS by Western blot, both LC3-I and LC3-II were significantly up-regulated compared with cells cultured as monolayers. The functional autophagic flux was confirmed by immunoblots of LC3 and p62 (SQSTM1/sequestosome1) in cells treated with Bafilomycin A1 (5 nM). MCS were fixed and included in paraffin to analyze the expression of LC3 and observed a differential localization of autophagic cells, increasing towards the center of the spheroid, correlating with the hypoxic population previously described. Uppon Tz adittion at a concentration of 50 ug/ml, a higher and uniform expression of LC3 was found in all the living cells. These observations were further supported by the finding that p62 was down-regulated in Tz treated spheroids in opposition to controls (commercial IgG). In 2D, Tz (1 ug/ml) also exerted LC3-II conversion and increase in autophagosomes formation. Autophagy inhibition by 3-methiladenine (3-MA) used at 1 mM, in combination with Tz decreased two fold vs Tz alone in monolayers (49% vs 76% cell viability respectively, p Citation Format: Cristina E Rodriguez, Sara Reidel, Elisa D Bal de Kier Joffe, Maria A Jasnis, Gabriel L Fiszman. Autophagy in three dimensional cultures provides survival advantage against trastuzumab in HER2+ mammary adenocarcinoma cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-05-09." @default.
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- W1547094328 date "2015-04-30" @default.
- W1547094328 modified "2023-10-14" @default.
- W1547094328 title "Abstract P5-05-09: Autophagy in three dimensional cultures provides survival advantage against trastuzumab in HER2+ mammary adenocarcinoma cells" @default.
- W1547094328 doi "https://doi.org/10.1158/1538-7445.sabcs14-p5-05-09" @default.
- W1547094328 hasPublicationYear "2015" @default.
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