Abstract 3288: A chromosome engineering mouse model to identify mechanisms by which duplication of 8q24 promotes human breast cancer
Authors: Tseng Yuen-Yi , Beadnell Thomas , Schwertfeger Kathryn , Bagchi Anindya 
Published: August 2012

Abstract
The early latency and poor prognosis of human breast cancer is often associated with the gain of extra copy of 8q24 locus containing the c-Myc oncogene. Evaluation of aberrations at the 8q24 locus by high-resolution SNP array identified a 2.1 Mb region which only includes the c-Myc, Pvt1, and Gsdmc genes. Interestingly, the transgenic c-myc mouse has shown that the overexpression of c-myc alone is not sufficient to develop the mammary adenocarcinoma, suggesting that the overexpression of c-myc may not truly reflect breast cancer patients who were diagnosed with low copy-number gain of 8q24. It also implies that the Pvt1 or Gsdmc may play an important role with the c-Myc during tumor progression. However, functional analysis of this 2.1 Mb interval of 8q24 has been limited by a lack of suitable mouse models. Here, we report a novel mouse model, namely c-myc-gsdmcdp/+ (3N), containing the extra copy-number gain of 2.1 Mb interval as observed in breast cancer patients. To demonstrate the effect of the 3N gain, we have performed in vitro mammary epithelium experiments and in vivo mammary gland analyses in female virgin mice at 6 and 10 weeks of age. Interestingly, the mouse mammary epithelium with the 3N gain displays above 3 fold expression of c-Myc and Pvt-1 and significantly larger acinar structures in three-dimensional (3D) culture compared to the wild type (wt). Moreover, we found that mammary glands from 3N mice show excessive side-branching as early as 6 weeks. In 10 weeks, mammary glands from 3N mice display not only excessive side-branching but also precocious lobulo-alveolar development and contain numerous epithelial cells that are hyperproliferative as demonstrated by BrdU incorporation analysis when compared to wt. Using combined stem cell markers, the mammary stem cells (MaSCs)/progenitor cells-enriched population was expanded in mammary tissue from 3N mice, suggesting that a higher number of MaSCs deregulates a branching network between ducts and lobulo-alveolar structures similarly to other premalignant mouse models. Strikingly, further molecular mechanistic investigation shows that increased expression of c-myc and pvt1 promotes upregulation of epithelial-mesenchymal transition markers in mammary glands from 3N mice. Previous studies have reported that ∼40% of HER2+ breast cancers have a low copy-number gain of 8q24. Therefore, we crossed our 3N mice with MMTVneu transgenic mice. In these double-mutation mice, we observed accelerated malignant properties in 3D culture and migratory analyses. These results suggest that low copy number-gain of 8q24 may collaborate with Her2 oncogenic pathway to accelerate malignant transformation. Thus, our 3N mouse model establishes a new milestone in explaining how the low copy-number gain of 8q24 participates breast carcinogenesis and will be further analyzed to determine how aggressive tumor phenotypes are linked to poor clinical outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3288. doi:1538-7445.AM2012-3288