title: Three-dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer.
abstract: A 3D microtissues using T47D and JIMT-1 cells were generated to analyze tissue-like response of breast cancer cells after combined human epidermal growth factor receptor 2 (HER2)-targeted treatment and radiation. Following lentiviral knockdown of HER2, we compared growth rate alterations using 2D monolayers, 3D microtissues, and mouse xenografts. Additionally, to model combined therapeutic strategies, we treated HER2-depleted T47D cells and 3D microtissues using trastuzumab (anti-HER2 antibody) in combination with irradiation. Comparison of HER2 knockdown with corresponding controls revealed growth impairment due to HER2 knockdown in T47D 2D monolayers, 3D microtissues, and xenografts (after 2, 12, and ≥40 days, respectively). In contrast, HER2 knockdown was less effective in inhibiting growth of trastuzumab-resistant JIMT-1 cells in vitro and in vivo. Combined administration of trastuzumab and radiation treatment was also analyzed using T47D 3D microtissues. Administration of both, radiation (5 Gy) and trastuzumab, significantly enhanced the growth inhibiting effect in 3D microtissues. To improve the predictive power of potential drugs--as single agents or in combination--here, we show that regarding tumor growth analyses, 3D microtissues are highly comparable to outcomes derived from xenografts. Considering increased limitations for animal experiments on the one hand and strong need of novel drugs on the other hand, it is indispensable to include highly reproducible 3D microtissue platform in preclinical analyses to validate more accurately the capacity of future drug-combined radiotherapy.
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Falkenberg
authors.affiliation: Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Höfig
authors.affiliation: Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosemann
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Justine
authors.initials: J
authors.lastname: Szumielewski
authors.affiliation: Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Richter
authors.affiliation: Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Kenji
authors.initials: K
authors.lastname: Schorpp
authors.affiliation: Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Hadian
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aubele
authors.affiliation: Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.|Radiation Biology, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
authors.affiliation: Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Nataša
authors.initials: N
authors.lastname: Anastasov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D011827:Radiation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency; D046509:Tissue Culture Techniques; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: 3D microtissue; HER2 knockdown; combination; model; mouse xenografts; radiation; spheroid; trastuzumab