Abstract 4486: Reexpression of LSAMP, a gene frequently deleted in African American prostate cancers, alters adhesive qualities of prostate tumor cells and inhibits Akt, ERK1/2, and β-Catenin signaling axis
Authors: Babcock Kevin , Rosner Inger L. , Srivastava Shiv , Dobi Albert , Tan Shyh-Han 
Published: August 2018

INTRODUCTION: Although African American (AA) men have the highest prostate cancer (CaP) incidence and mortality rates in the US, most studies of CaP genome have been performed using tumor specimens from Caucasian Americans (CA). To address the underrepresentation of AA CaP in these studies, we performed whole genome sequencing, IHC and FISH validation on tissue microarrays, and analysis of TCGA data, on a total of 438 CaPs. We noted less frequent alterations of two common CaP driver genes, PTEN and ERG, in CaP genomes of AA compared to CA men, confirming earlier observations by others and us. We reported a higher frequency of a genomic deletion of the Limbic System Associated Membrane Protein (LSAMP) gene, located on 3q13.31 locus in AA CaP, which was also associated with rapid biochemical recurrence. A recent study of CaP genome in a Chinese cohort detected LSAMP alterations at a frequency similar to that in our AA cases. LSAMP loss in other cancers have been associated with aggressive disease. We hypothesize that the loss of LSAMP contributes to CaP progression. Here, we report further biological evaluations of LSAMP modulation in CaP cells.

METHODS: The copy number and expression of LSAMP in CaP cell lines were assessed. We established stable doxycycline inducible LSAMP expression in LNCaP and in MDA PCa 2b cells (AA patient derived cell line with monoallelic LSAMP deletion), and constitutive expression in DU145 cells. We assessed the effect of LSAMP expression on cell-cell adhesion by monitoring the binding of LSAMP expressing and control DU145 cells to mouse fibroblast (NIH-3T3), normal human prostate stroma (WPMY-1), human endothelial (HUVEC), and human bone marrow stroma (HS-5) cells. We analyzed LSAMP modulated signaling pathways in the inducible and constitutively LSAMP expressing cell lines by immunoblot and immunofluorescence assays.

RESULTS: Overexpression of LSAMP resulted in attenuated cell proliferation and increased adhesion of cells to extracellular matrix proteins. LSAMP expression in DU145 cells increased their adhesion to fibroblast and prostate stroma cell lines, and concomitantly decreased their adhesion to endothelial, and bone marrow stroma cells. LSAMP expression resulted in decreased expression of FGFR2, FGFR4, and EphA3 receptor tyrosine kinases, and decreased phosphorylation of their downstream targets in Akt and ERK1/2 signaling pathways, leading to the inactivation of β-catenin. LSAMP expression also alters the levels of some Integrins.

CONCLUSION: Cell biologic features of LSAMP reported here, along with observations of genomic inactivations of LSAMP in CaP support its role in CaP progression through altered cell adhesion. These data provide the first insight into LSAMP function in CaP, corroborating with studies that suggest bona fide tumor suppressor function for LSAMP in cancers.

Citation Format: Kevin Babcock, Inger L. Rosner, Shiv Srivastava, Albert Dobi, Shyh-Han Tan. Reexpression of LSAMP, a gene frequently deleted in African American prostate cancers, alters adhesive qualities of prostate tumor cells and inhibits Akt, ERK1/2, and β-Catenin signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4486.