Abstract 3300: MYC regulation of a “poor prognosis” metastatic cancer cell state

Abstract

Gene expression signatures are used clinically as prognostic tools to determine the risk of individual patients with localized breast tumors developing distant metastasis. However, we lack a clear understanding of whether these correlative biomarkers link to a common biological network that regulates metastasis. METHODS: In order to address this question, we analyzed thirteen different well-described (including two in clinical use) “poor outcome” cancer signatures in a cell line model of estrogen receptor positive breast cancer (MCF7) manipulated by diverse oncogenic stimuli. RESULTS: We find that the c-MYC oncoprotein coordinately regulates the expression of these thirteen different “poor outcome” cancer signatures. In addition, functional inactivation of MYC in human breast cancer cells specifically inhibits their distant metastasis in vivo and invasive behavior in vitro. CONCLUSION: These results suggest that MYC oncogene activity, as reflected by “poor prognosis” signature expression, may be necessary for the translocation of “poor outcome” human breast tumors to distant sites. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3300.

Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

“…(G) NSM activity in lysates of NIH 3T3-vector (Vector) and -c-src Y527F (Src) cells measured by an assay kit from Echelon. (H) Expression of indicated genes (Affymetrix U133Plus2.0) in cells transduced with an empty retrovirus (Vector) or pBabe encoding for ERBB2 and grown in medium supplemented with 2% horse serum for 26 hr (Wolfer et al, 2010). When indicated cells transduced with empty vector were treated with 50 ng/ml EGF for 2 hr before harvesting.…”

“…Of note, the transformation-associated decrease in the expression of SMPD1 was not limited to the model systems used here. An analysis of a published gene expression microarray data set (Wolfer et al, 2010) revealed ERBB2-and epidermal-growth-factor-induced decrease in SMPD1 mRNA levels in MCF10A breast epithelial cells (Figure 5H), and a database search demonstrated a highly significant cancer-associated reduction in SMPD1 expression in numerous microarray studies comparing mRNA levels in tumors originating from gastrointestinal tract, liver, head and neck, kidney, pancreas, cervix, lung, brain, and lymphoid tissue with their appropriate control tissues ( Figure S2). Also SMPD3 mRNA levels were significantly reduced in gastrointestinal and lung carcinomas as well as in diffuse large B cell lymphomas ( Figure S2).…”

Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC

“…We next investigated whether EN4 affects MYC-regulated transcriptional targets in 231MFP breast cancer cells. These highly aggressive and tumorigenic triple-negative breast cancer cells are derived from MDA-MB-231 cells that have been previously shown to be driven by MYC (Horiuchi et al, 2012;Wolfer et al, 2010;Xu et al, 2010). We performed RNA sequencing (RNA-seq) on EN4-treated 231MFP cells to identify gene expression changes (Figures 4C and 4D).…”