BRMS1-Mediated Suppression of Metastases in p53 Mutant Lung Adenocarcinoma

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In LUAD p53 mutations occur more commonly (45%) than Kras, EGFR, or ELM4/ALK genomic perturbations, combined. Previously we have shown that BRMS1-mediated suppression of cell migration and invasion is associated with loss of p53. An unbiased analysis of the TCGA database reveals low BRMS1 expression is associated with a poor progression-free survival in p53mut LUAD, not p53WT, and in LUAD with a solid histologic subtype. Gene expression arrays confirm that BRMS1KD correlates with multiple p53 regulated genes involved in migration and invasion. In this proposal we provide the first evidence that BRMS1transcriptionally regulates the metastasis-related p53-target genes, such as Maspin and Serpine1, in p53mut LUAD. Increases in Maspin or down-regulation of Serpine1 contribute to BRMS1-mediated metastasis suppression. Moreover, inhibition of BRMS1 degradation using the CK2 inhibitor CX4945 results in significantly less cell migration and invasion in p53mut compared to p53WT LUAD cells. The goal of this proposal is to understand the transcriptional mechanisms of BRMS1-mediated suppression of metastases in p53mut LUAD. Using patient-derived samples we plan to discern the contribution of BRMS1 to the development of metastases and assess the therapeutic significance of targeting BRMS1 in p53mut LUAD with specific histological subtypes.

BMSR1 Models

A. CK2a’-induced BRMS1 degradation promotes metastasis of NSCLC in vivo. A, induction of CK2a’ promotes distant metastasis of NSCLC. H157 stable cell lines were orthotopically injected into the left lung of mice. Mouse bioluminescent CT images show the growth of tumor and metastatic sites in three representative mice in each group (1–3, control; 4–6, BRMS1WT without doxycycline; 7–9, BRMS1WT with doxycycline (Doxy.); 10–12, BRMS1S30A with doxycycline). The scale indicates the signal intensity cell quantification. B. activation of CK2a’ induces metastasis of tumors with BRMS1 wild-type. The graph represents fold changes of metastasis burden over control group 43 days postinjection. (Cancer Res 2016)