Abstract 3282: Molecular characterization of a panel of patient-derived breast cancer xenografts
Authors: Torsten Giesemann, Rebekka Krumbach, Julia Schüler, Vincent Vuaroqueaux, Michael Hofmann, Ningshu Liu, Andrea Haegebarth, Thomas Beckers, Heinz-Herbert Fiebig
Journal: Cancer Research (2010)

Abstract Breast cancer is a heterogeneous disease for which several subtypes have been described according to histological and molecular determinants. Therapeutic decisions are dependent on tumor staging which includes molecular markers like estrogen receptor (treatment with anti-estrogens or aromatase inhibitors) or HER2 (treatment with HER2 targeting agents Trastuzumab or Lapatinib). Here we present a panel of 12 patient-derived breast cancer xenografts, eleven of which have been established by Oncotest from primary patient material. Molecular profiling included expression analysis of receptors for estrogens (ER), androgens (AR) and progesterone (PR), HER2 and the E2F transcription factor 1 by quantitative RT-PCR and Affymetrix HG U133 plus2.0 array analysis. HER2 protein and phosphorylation were determined by ELISA and - for selected models - FISH analysis was performed to determine gene amplification. MAXF 713 and MAXF 1398 are ER positive, luminal B subtype tumors, whereas MAXF 1162 is a HER2-overexpressing, Lapatinib sensitive tumor. The high HER2 levels in MAXF 1162 are based on a gene amplification. MAXF 1322 is borderline HER2-positive, but insensitive towards Lapatinib and Herceptin. The majority of tumor models (8 out of 12) belong to the basal-like, triple negative breast cancer subtype. In addition, activation of downstream signaling molecules of the Akt and MAPK pathways (Akt, Erk1/2 and p70S6K) were analysed. Akt signaling is important in many breast cancers and 8 out of 12 tumor models depicted activated Akt, some of which also had highly activated p70S6K. Erk1/2 phosphorylation was less prominent and slightly higher compared to the Oncotest lysate pool in MAXF 1322. The Oncotest lysate pool incorporates 106 different tumor lysates and proved to be a valuable control lysate to estimate a mean expression and/or activation level. Finally, the mutational status of PI3Kα and PTEN was assessed with PTEN protein expression also evaluated by Western Blot. Modifications in the PI3Kα activity and its negative effector PTEN modulate Akt kinase activity and downstream signaling. Finally, the estrogen-dependency of the ER-positive models MAXF 713 and MAXF 1398 and their growth properties in dependence of subcutaneous versus orthotopic implantation were assessed. The xenograft models are routinely implanted subcutaneously, which sustains tumor growth. Nevertheless we found that of the 12 MAXF models as studied, 4 grew faster when implanted orthotopically into the mammary fat pad. In summary, a unique collection of patient-derived mammary xenograft models has been characterised comprehensively in order to enable a pre-study selection of suitable tumors for in-vivo efficacy testing. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3282.