Abstract C56: The combined loss of SSeCKS/Gravin/AKAP12 and Rb in the prostate promotes spontaneous lymph node metastases with basal-luminal transitional phenotypes

Abstract

Abstract Introduction: Previous data indicated that the loss of SSeCKS/Gravin/AKAP12 (“SSeCKS”) or Rb correlates with prostate cancer (CaP) progression and that their deletion results in increased prostatic hyperplasia (1,2). SSeCKS re-expression in MAT-LyLu prostate cancer cells has little effect on the growth potential of primary-site tumors and on the ability of metastatic cells to colonize distal sites, yet it suppresses the growth of macrometastases by suppressing tumor-encoded vascular endothelial growth factor expression and neovascularization of the metastatic niche(3). We demonstrated recently that SSeCKS-null (Akap12−/−) mouse embryo fibroblasts (KO-MEF) suffer from an Rb-dependent premature senescence, and that the hyperplastic prostates in KO mice exhibit markers of increased senescence (4). Experimental Procedures: In order to determine whether SSeCKS and Rb act synergistically to promote CaP progression, KO mice were crossed to mice with prostate-specific conditional Rb deletion (Pb-Cre;Rbfl/fl). Results: Compared to controls (WT, Akap12−/− or Pb-Cre;Rbfl/fl mice), 100% of Akap12−/−;Pb-Cre;Rbfl/fl male mice showed evidence of low grade prostatic intraepithelial neoplasia (LG-PIN), with a smaller percentage (22%) displaying high grade (HG) PIN by 10 months of age. These lesions were marked by increased levels of cytoplasmic E-cadherin (compared to the cell-cell junctional staining in normal or hyperplastic luminal prostate layers) in LGPIN and by the loss of E-cadherin expression in HG-PIN. Unexpectedly, Akap12−/−;Pb-Cre;Rbfl/fl males showed increased numbers (1.8- to 2.5-fold) of p63-positive basal cells in all four lobes compared with control mouse prostates. Importantly, whereas control mice showed neither primary-site prostate cancer nor lymph node (LN) metastasis, >/80% of the Akap12−/−;Pb-Cre;Rbfl/fl males displayed metastases in pelvic or inguinal LN. These metastases did not stain for E-cadherin, but were positive for both basal (5 and 14) and luminal (8) cytokeratins, and low levels of androgen receptor. Foci within these lesions were positive for the basal marker, p63, and for the mesenchymal marker, vimentin. The LN lesions contained deletions of their floxed Rb loci, as shown by nested PCR assays, corroborating that they derived from the transgenic prostate cells. Conclusions: The combined loss of SSeCKS and Rb leads to early CaP initiation marked by increased basal cell proliferation in all four lobes, as well as the marked increase in LN metastasis of tumor cells with a basal-luminal transitional phenotype. These data strongly suggest that SSeCKS suppresses parameters of CaP initiation and metastasis. Citation Format: Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, Barbara Foster, Irwin H. Gelman. The combined loss of SSeCKS/Gravin/AKAP12 and Rb in the prostate promotes spontaneous lymph node metastases with basal-luminal transitional phenotypes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C56.