Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

ABSTRACT: The dire need for more effective treatments for clinically aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology. Breast cancers that are “triple-negative” for the clinical markers, ESR1, PGR, and HER2, typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency, and predisposes highly penetrant, metastatic, adenocarcinomas. These tumors are poorly differentiated with histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Transcriptomic analyses demonstrated that the tumors shared attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader triple-negative category defined by clinical markers. Ex vivo tumorsphere formation, which was suppressed by Notch and Wnt pathway inhibition, and tumor antigen profiles and are consistent with enrichment of stem-like and luminal progenitor cells among these tumors. These studies establish a novel mouse model of malignant breast cancer based on events in the human disease and underscore the non-reciprocal requirements of three canonical tumor suppressor pathways in breast cancer evolution. Morphogenetic pathways may provide additional avenues for targeted therapeutic intervention. Gene expression analysis of mouse mammary tumors with perturbation of Rb family pathways, p53, and/or Brca1 are compared to other mouse model tumors (n=152)

ORGANISM(S): Mus musculus

SUBMITTER: Karl Simin

PROVIDER: E-GEOD-34479 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

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Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

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