Abstract 2905: The HMGA1-MMP-2 pathway in poorly differentiated uterine tumors

Abstract

Abstract Uterine cancer is the most common cancer of the female genital tract and the fourth most frequent cause for cancer death in women in the United States. Thus, further study has the potential to significantly benefit women's health worldwide. Despite the high prevalence of this disease, the molecular events that lead to uterine cancers are poorly understood. We are studying the role of the high mobility group A1 (HMGA1) gene in the pathogenesis of uterine cancer. The HMGA1 gene encodes the HMGA1a and HMGA1b chromatin remodeling proteins, which function in modulating gene expression. In a previously published pilot study, we showed that HMGA1 is overexpressed in poorly differentiated uterine cancers, but not in normal uterine tissue, benign tumors, or most low-grade neoplasms of the uterus. We also engineered HMGA1 transgenic mice and found that all females develop uterine sarcomas by 9 months of age. In lung cancer, we reported that HMGA1 induces expression of the matrix metalloproteinase-2 (MMP-2) gene, but only in poorly differentiated tumors, suggesting that this pathway could drive tumor progression and a poorly differentiated state. Here, we investigated the role of the HMGA1-MMP-2 pathway in the pathogenesis of uterine tumorigenesis. Using a genetic approach, we crossed our HMGA1 transgenic mice with mice that are null for the MMP-2 gene. We found that the uterine tumors were significantly smaller in the HMGA1 transgenic mice that are also null for MMP-2. To determine if this pathway is involved in human uterine tumorigenesis, we assessed expression of the HMGA1 and MMP-2 genes in primary, human uterine tumors. We studied: 1.) endometrioid tumors, which are derived from the endometrial epithelium and tend to be low-grade (well-differentiated), 2.) serous tumors, which are also derived from the endometrial epithelium, but tend to be high-grade (poorly differentiated), and, 3.) carcinosarcomas (or mixed malignant, mullerian tumors), which are derived from the endometrial epithelium and stroma and tend to by high-grade. We found that HMGA1 expression was highest in the high-grade serous tumors and carcinosarcomas, with lower levels in the endometrioid tumors. Moreover, we found that there was a significant correlation between HMGA1 and MMP-2, but only in the high-grade carcinosarcomas and serous tumors. Taken together, our studies demonstrate that HMGA1 induces expression of MMP-2 during uterine tumorigenesis and suggest that this pathway is important in aggressive, poorly differentiated tumors. Although further studies are needed, our findings also suggest that the HMGA1-MMP-2 pathway could serve as a rational therapeutic target in poorly differentiated uterine cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2905. doi:10.1158/1538-7445.AM2011-2905