Abstract A10: Oncogenomic analysis of IGF-IR driven mammary tumors identifies a potential cell of origin and mechanisms of tumor recurrence

Genetically engineered mice are valuable tools for understanding the genetic events that contribute to breast cancer development and progression. We have previously generated a doxycycline (Dox) inducible model of breast cancer, MTB-IGFIR, in which overexpression of the human type-I IGF receptor (IGF-IR) leads to the rapid induction of ER-mammary tumors with mixed luminal and basal features. Following Dox withdrawal and subsequent transgene downregulation, a subset of tumors escape IGF-IR dependence and spontaneously recur with evidence of an epithelial-mesenchymal transition (EMT). To gain insight into the molecular pathways that drive primary and recurrent tumor growth in MTB-IGFIR mice, we carried out gene expression profiling and DNA copy number analysis. Gene-set enrichment analysis (GSEA) revealed expression of an Akt oncogenic signature in primary tumors, consistent with downstream signaling mediated by IGF-IR. Interestingly, primary tumors also expressed a luminal progenitor gene signature suggesting a potential cell of origin. Accordingly, flow cytometric analysis of Dox-pulsed mice showed that high expression of the IGF-IR transgene was confined to EpCAM+/high Sca-1– cells, a putative ER- alveolar progenitor population. Recurrent tumors were found to express a mammary stem cell (MaSC) gene signature, which is consistent with their more mesenchymal phenotype as well as increased cell cycle pathway activity. While aCGH analysis identified few genomic changes in ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research