Abstract 3524: Unraveling the dichotomy of Runx1 in breast cancer

Abstract

Abstract Each of the Runx family of transcription factors (Runx1, Runx2 and Runx3) is associated with specific human cancers. Recent genetic evidence suggests that Runx1 plays an important role in human breast cancer. It has been shown to be frequently mutated in certain breast cancer subtypes, and an inverse correlation between Runx1 expression and increasing tumor grade was established. Although Runx1 is considered to be a tumor suppressor, one study suggests otherwise, with loss of Runx1 in epithelial cancer cell lines impairing tumor growth. Thus, the dichotomous nature of Runx1 during breast cancer progression and metastasis remains ambiguous. Using the MMTV-PyMT transgenic mouse model of breast cancer and complementary in vitro models, we are further defining the role of Runx factors, particularly Runx1, in breast cancer progression. MMTV-PyMT mice and age- matched controls were sacrificed at multiple time points (4-15 weeks) representing all stages of disease progression. Mammary gland (primary site), tumor and lung (metastatic site) were excised and analyzed: Runx1 RNA and protein expression in the mammary gland was significantly increased over controls as early as 8 weeks. This increase persisted throughout the course of the disease with Runx1 levels being highest at late time points (13 and 15 weeks), concomitant with the presence of metastatic lesions in the lung. During tumor progression, Runx1 (and to a lesser extent, Runx2) levels were consistently elevated. In the lungs, Runx1 (and Runx2) protein expression significantly increased as a function of the number/size of metastatic lesions present. Furthermore, phenotypic analyses as well as relevant RNA/protein expression were determined in both normal mouse mammary gland epithelial cells (NMuMG) and an MMTV-PyMT tumor-derived cell line (MMTV): MMTV cells exhibited superior rates of growth, invasion and migration and expressed 3-fold more Runx1 (yet only half as much Runx2) than NMuMG cells; complementary knockdown studies were used to reveal the contribution of Runx1 to these processes. Additionally, analysis of microRNA expression using microRNA arrays and QPCR in both mouse and cell line models revealed the potential for specific microRNAs in the temporal regulation of Runx factors during breast cancer progression. Overall, our results support roles for Runx factors, particularly Runx1, in breast cancer. Notably, increased Runx1 expression is associated with disease progression and metastasis as well as a more aggressive phenotype in our models. Moreover, in our disease models potential regulation of Runx factors by specific microRNAs is demonstrated. Taken together, these data highlight Runx1 as a promising novel therapeutic target in breast cancer. Citation Format: Gillian Browne, Nicole M. Bishop, Jason R. Dobson, Sharath C. Madasu, Farina H. Nicholas, Maria L. La Porta, Dana Frederick, Jennifer L. Colby, Leslie M. Shaw, Justine Landis, Janet L. Stein, Jane B. Lian, Gary S. Stein. Unraveling the dichotomy of Runx1 in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3524. doi:10.1158/1538-7445.AM2014-3524