Abstract Glycodelin is a secreted lipocalin family glycoprotein, expressed mainly in differentiated epithelia in reproductive tissues. The expression of glycodelin in breast and endometrial cancer cells induces cell differentiation. We have found that transfection of glycodelin cDNA into MCF-7 breast cancer cells changes cellular morphology and gene expression towards less malignant direction. In pre-clinical xenograft mouse model glycodelin-producing cells formed significantly smaller tumors with lower proliferation rate than control cells. This is in keeping with the association of glycodelin with well-differentiated and less proliferative tumors in sporadic breast cancer patients. The aim of the present study is to elucidate the mechanism(s) mediating glycodelin-induced differentiation of breast cancer cells. The gene expression changes between glycodelin-producing and control cells were compared using a cDNA micro array. The cells were grown on Matrigel with and without protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), PKCΔ inhibitor Rottlerin and various other kinase inhibitors. PKCΔ was also down-regulated with RNAi. The levels of PKCΔ were measured using Western Blotting. The gene expression changes induced by glycodelin were enriched in several pathways, including mitogen-activated protein kinase (MAPK) -pathway. Among various studied proteins of MAPK-pathway, we found that phosphorylated PKCΔ was down-regulated in glycodelin-producing cells. Further studies with activators and inhibitors indicated that addition of PKC activator PMA to cell culture medium induced dramatic morphological changes and increased motility of the control cells, while glycodelin-producing cells were unresponsive. The effect of PMA was abolished by Rottlerin, an inhibitor of PKCΔ, as well as by using siRNA for PKCΔ. These results suggest that the glycodelin-induced differentiation of breast cancer cells is mediated by PKCΔ, which in other studies has been proposed to be a potential target for cancer treatment. 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 1961. doi:10.1158/1538-7445.AM2011-1961