Abstract Umbilical cord matrix stem cells (UCMSC) represent a promising source of therapeutics for various diseases including cancer. We have shown that naïve rat UCMSC significantly attenuate Fisher 344 rat-derived mammary adenocarcinoma (Mat B III) cell proliferation both in vivo and in vitro. To study the underlying mechanisms and genes involved in the Mat B III growth attenuation, we investigated gene expression profiles of naive rat UCMSC alone co-cultured with Mat BIII cells by cDNA microarray analysis. Total RNA was extracted from the naïve rat UCMSC alone and those co-cultured with Mat B III in transwell culture dishes. The comparison of gene expression profiles between untreated and co-cultured rat UCMSC identified five up-regulated (Follistatin (FST), Sulfatase1 (SULF-1), Glucose phosphate isomerase (GPI), HtrA serine peptidase (HTRA1), and Adipocyte differentiation-related protein (ADRP)) and two down-regulated (Transforming growth factor, beta-induced (TGFBI), Podoplanin (PDPN)) candidate genes based upon the following screening criteria: 1) candidate gene expression should show at least a 1.5 fold change in rat UCMSC co-cultured with Mat B III cells; 2) candidate genes encode secretory proteins; and 3) candidate genes encode cell growth-related proteins. Following confirmation of gene expression by real time-PCR, ADRP, SULF-1 and GPI were selected for further analysis. Addition of specific neutralizing antibodies against these three gene products individually or all together in the co-culture of Mat B III cells and 1/20 cell number of rat UCMSC significantly increased [3H] thymidine uptake in the Mat B III cells implying that these gene products are functionally produced under the co-cultured condition and attenuate cell growth. Immunoprecipitation followed by Western Blot analysis demonstrated that these proteins are indeed secreted into the culture medium. We are investigating the siRNA-dependent down regulation of these genes in rat UCMSC to confirm their tumor suppressor function. These results suggest that ADRP, SULF-1 and GPI act as tumor suppressor genes and these genes might be involved in rat UCMSC-dependent growth attenuation of rat mammary tumor. This work was supported by the Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research, KSU College of Veterinary Medicine Dean's Fund, NIH P20 RR017686, p20RR1556, R21CA135599, Kansas Bioscience Authority research fund and by the Intramural Research Program of the NIH, National Institute on Aging. 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 3355. doi:10.1158/1538-7445.AM2011-3355