Abstract B18: Role of the tumor suppressor gene DLC-2 in ERBB2 induced mouse mammary tumorigenesis and metastasis

Abstract

Abstract Introduction: Overexpression of dominant oncogenes and the loss of tumor suppressor genes are basic genetic events in acquisition of the malignant phenotype. The ERBB-2 proto-oncogene is overexpressed in 20% - 30% of human breast cancers. The tumor suppressor gene Deleted in liver cancer 2 (DLC-2, also known as STARD13) maps to chromosome 13q12.3 and is frequently downregulated by 72% in human breast cancer. It encodes a RhoGAP protein containing a START lipid binding domain. It is not known what role DLC-2 silencing plays in breast carcinogenesis. The purpose of our study is to assess the biological significance of inactivation of DLC-2 in ERBB2 induced mammary tumorigenesis mouse model. For this, we used MMTV-NIC mice, which carry an activated NEU oncogene (ERBB2) under control of the MMTV-LTR promoter that also co-expresses Cre recombinase. These mice were crossed to a conditional DLC-2 knockout mouse (floxed exon 3). Objectives: To determine if heterozygous or homozygous DLC-2 loss plays a role in mouse mammary tumor progression in MMTV-NIC mice. Results: Our preliminary results showed that heterozygous deletion of DLC-2 in the mammary epithelium of the MMTV-NIC mouse model resulted in increased tumor burden with accelerated tumor growth. Metastases to the lungs were quantified by scanning H&E stained step sections (4X150uM). We observed a significant increase in the incidence of lung metastases in heterozygous DLC-2 exon3floxed/+ MMTV-NIC mice. The lung metastases showed a homogenous morphology and histopathologically similar phenotype to the MMTV-NIC strain. DLC-2 heterozygous tumor cells showed increased tumorosphere formation under low-attachment conditions with minimal growth factor supplementation. These tumor cells also showed increased expression of mesenchymal cell markers, as determined by quantitative real time RT-PCR, suggesting an Epithelial to Mesenchymal transition is occurring. Experiments with homozygous floxed DLC-2 mice are ongoing and will be presented. Conclusion: These results indicate that loss of one allele of DLC-2 is sufficient to accelerate NEU oncogene induced tumorigenesis. Citation Format: Pratima Basak, Pratima Basak, Heather Leslie, Heather Leslie, Afshin Raouf, Afshin Raouf, Michael RA Mowat, Michael RA Mowat. Role of the tumor suppressor gene DLC-2 in ERBB2 induced mouse mammary tumorigenesis and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B18.