Abstract B50: HOXB7 modulates tumor cell invasion and is a predictor of poor clinical outcome in pancreatic cancer.

Abstract

HOX genes encode transcription factors that not only regulate normal growth and differentiation during embryonic development, but also promote oncogenesis through their aberrant expression and functional deregulation in cancer. Published microarray data indicate multiple HOX genes are aberrantly expressed in pancreatic adenocarcinoma (PDAC), although it is largely unknown whether these changes in expression directly influence pancreatic tumorigenesis. Given its known pro-tumorigenic effects in various other types of cancer, HOXB7 expression and function was examined in pancreatic cancer. Both HOXB7 protein and message levels were examined in PDAC cell lines and patient tumors and found to be significantly elevated relative to normal pancreas. Immunohistochemical evaluation of a large tissue microarray of 145 PDAC patient tumors demonstrated that higher levels of HOXB7 expression was associated with lymph node metastasis (P = 0.034) and worse overall survival (median survival 18.7 ± 2.5 months vs. 28.8 ± 2.9 months, log-rank P=0.008), as well as a statistically significant independent predictor of decreased survival in multivariate analysis (Hazard Ratio = 1.56, 95% CI 1.02-2.39, P=0.04). Exploring possible mechanisms underlying these finding, the phenotypic effects of HOXB7 overexpression and silencing were examined by various in vitro assays of biological activity. While HOXB7 had no significant impact on PDAC cell line growth or survival, it strongly promoted the migratory and invasive phenotypes of multiple PDAC cell lines. Gene microarray analysis of PDAC cell lines following siRNA-mediated HOXB7 gene knockdown revealed multiple candidate genes whose expression were linked to HOXB7 expression and that have the potential to explain the proinvasive and protumorigenic activities of HOXB7. In conclusion, HOXB7 and its downstream transcriptional gene targets promote invasive phenotype and aggressive clinical behavior in PDAC and therefore represent potentially useful clinical biomarkers or targets of therapy for PDAC. Citation Format: Michael A. Arensman, Anne N. Kovochich, Timothy Donahue, Samuel W. French, David W. Dawson. HOXB7 modulates tumor cell invasion and is a predictor of poor clinical outcome in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B50.