Role of JHDM1B in Breast Cancer Development and Progression - AIRC IG 11416

Cell growth and proliferation are closely coupled to rRNA synthesis/ribosome biogenesis, and remarkably these processes are frequently de-regulated in cancer. rDNA transcription can be controlled by epigenetic modifications of chromatin, mainly histone modifications. Among these, methylation/demethylation of specific residues of lysine within histone H3 (H3K4, K9, K27 and K36) are closely correlated to cancer progression. The nucleolar protein Jumonji Histone DeMethylase 1B (JHDM1B ) plays a crucial role in the repression of rDNA transcription. Several in vitro studies showed that a reduction of JHDM1B levels determines a perturbation of cell proliferation, indicating that JHDM1B reduction might contribute to the increased cell growth/proliferation. Accordingly, we have preliminary results on a group of primary breast cancers, a tumor type whose clinical behaviour is influenced by the rate of ribosome biogenesis, indicating that JHDM1B expression in the tumor is correlated with disease specific survival, the outcome of patients characterized by low JHDM1B levels being worse. Moreover we observed in vitro in breast cancer derived cell lines that transient JHDM1B Knock Down (KD) determined an increase in ribosome biogenesis, which did not correlate directly with cell proliferation. In fact in p53-wt breast cancer cell lines JHDM1B KD determined a slower propagation compared to control cells; this biological behavior could be explained in part by a higher rate of cell death and in part by an increased occurrence of replicative senescence and replicative block in G2/M phase. On the contrary, JHDM1B KD in p53-compromised cell line determined a surge in cell proliferation compared to control cells. Here we propose to investigate the contribution of JHDM1B to epithelial mammary cell transformation and malignant progression, dissecting the role of p53 in mediating JHDM1B reduction effects, and to define of the relevance of JHDM1B in human breast cancers. The three-year research program is organized into four tasks, addressing (1) the biological effect of JHDM1B knock-down on the transcription of rDNA genes, and whether such effect can be dependent, and in which way, by the status of p53; (2) the contribution of JHDM1B to the transformation of mammary gland epithelial cells; (3) the contribution of JHDM1B to breast cancer progression; (4) the relevance of JHDM1B alterations in human breast cancer clinical behavior. The accomplishment of the proposed tasks could provide the knowledge currently lacking regarding the mechanisms through which JHDM1B may act in cancer cells and their relevance in breast cancer.