Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.

Adam D Pfefferle,Elaine R Mardis,Jason I Herschkowitz,Jeffrey M Rosen,Krishna L Kanchi,Daniel C Koboldt,Yash N Agrawal,Charles M Perou

doi:10.1242/dmm.025239

Abstract

ABSTRACTTargeted therapies against basal-like breast tumors, which are typically ‘triple-negative breast cancers (TNBCs)’, remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3. As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.

Highlights

Human breast cancer is a heterogeneous disease that can be segregated into at least six distinct subtypes based on gene expression profiles: basal-like, claudin-low, human epidermal growth factor receptor 2 (HER2)-enriched, luminal A, luminal B and normal-like (Perou et al, 2000; Prat et al, 2010; Cancer Genome Atlas Network, 2012)
Trp53-null transplant tumors are counterparts for multiple expression subtypes of human breast cancer The Trp53-null transplant model produces phenotypically and genomically diverse tumors that can be classified into three major subtypes/classes based on gene expression profiles: p53nullBasalEx, Claudin-lowEx and p53null-LuminalEx (Pfefferle et al, 2013)
DISCUSSION increased public awareness and a greater understanding of tumor biology have led to improved patient survival rates, breast cancer is still the second leading cause of cancer related deaths in American women and triple-negative breast cancers (TNBCs) has the worst prognosis at present (Cancer Genome Atlas Network, 2012; Curigliano and Goldhirsch, 2011)

Summary

Introduction

Human breast cancer is a heterogeneous disease that can be segregated into at least six distinct subtypes based on gene expression profiles: basal-like, claudin-low, human epidermal growth factor receptor 2 (HER2)-enriched, luminal A, luminal B and normal-like (Perou et al, 2000; Prat et al, 2010; Cancer Genome Atlas Network, 2012). There is a growing appreciation for the consequences that TP53 gain-of-function mutations impose on cell signaling (Brosh and Rotter, 2009; Murphy et al, 2000), the majority of these TNBC TP53 mutations are predicted to lead to loss of function (Bullock and Fersht, 2001) This genetic foundation primes tumors to accumulate secondary genetic aberrations by decreasing the cell’s ability to maintain normal cell physiology (Murphy and Rosen, 2000; Hanel and Moll, 2012). Segregating genetic drivers of tumorigenesis from passenger aberrations is inherently difficult owing to the diversity of breast tumors and the large number of candidate aberrations identified in genome-wide profiling studies (Cancer Genome Atlas Network, 2012; Curtis et al, 2012)

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