Abstract 5305: Reexpression of LSAMP, a gene frequently deleted in African American prostate cancers, suppresses tumor growth and β-catenin activity

Abstract

Abstract Introduction: African American (AA) men have the highest prostate cancer incidence and mortality rates in the US. The biological contribution to this disparity, however, is not well understood. LSAMP inactivation has been implicated in several cancers, and was recently identified in prostate cancer. A higher frequency of LSAMP inactivation has been observed in AA prostate cancer, and this aberration has been associated with a significantly greater risk of disease progression. In the characterization of LSAMP in prostate cancer cells lines, we found the copy number to be variable and the expression to be low or undetectable. LNCaP, MDA PCa 2B, and DU 145 prostate cancer cell lines were stably transduced to express LSAMP in an inducible or constitutive manner. LSAMP expression in these cell lines resulted in reduced cell proliferation, and induced a reversion to indolent cell-cell, and cell-extra-cellular-matrix adhesion characteristics, consistent with its tumor suppressive role. LSAMP expression also resulted in the down-regulation of receptor tyrosine kinases EPHA3, FGFR2, and FGFR4, and reduced activation of their downstream ERK and AKT pathways. Several Integrins were also up-regulated upon LSAMP expression. Additionally, β-catenin localization was altered, suggesting a potential reduction in transcriptional activity. We assessed the tumor suppressive function of LSAMP further, using in vitro assays and in vivo mouse models. Methods: LSAMP expressing and control DU 145 cells were used to investigate the tumor suppressive function of LSAMP in vivo. Athymic nude mice were injected either subcutaneously, to determine effect of LSAMP expression on prostate tumor growth rates, or intravenously, to determine effect of LSAMP expression on tumor formation. We performed the TOPflash/FOPflash luciferase reporter assay to determine whether LSAMP expression modulates transcriptional activity of β-catenin in vitro. Results: LSAMP expression resulted in a significant inhibition of tumor growth in the subcutaneous xenograft model. In the intravenous xenograft model, LSAMP expression resulted in a reduced incidence of distant metastases. Consistent with the negative modulation of signal transduction, and β-catenin localization previously observed, LSAMP expression resulted in a reduction of β-catenin transcriptional activity in vitro. Conclusion: These studies provide in vivo evidence of the suppressive function of LSAMP in prostate tumors, corroborating previous in vitro and clinical findings. LSAMP expression reduced tumor growth rates, and incidence of distant metastases. LSAMP expression also reduced β-catenin transcriptional activity in vitro. These findings provide further support for a biological mechanism underlying the aggressive prostate cancer phenotype observed with LSAMP inactivation. Citation Format: Kevin Babcock, Taduru Sreenath, Charles P. Xavier, Inger L. Rosner, Shiv Srivastava, Albert Dobi, Shyh-Han Tan. Reexpression of LSAMP, a gene frequently deleted in African American prostate cancers, suppresses tumor growth and β-catenin activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5305.