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Cell Rep. 2019 Aug 6;28(6):1526-1537.e4. doi: 10.1016/j.celrep.2019.06.098.

A Spontaneous Aggressive ERα+ Mammary Tumor Model Is Driven by Kras Activation.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
2
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA.
4
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
5
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA; University of Wisconsin Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: linda.schuler@wisc.edu.
6
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address: obigriffith@wustl.edu.

Abstract

The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors in nulliparous females, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole-genome and exome sequencing in a discovery cohort (n = 5) of end-stage tumors revealed canonical activating mutations and copy number amplifications of Kras. The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% of tumors (23 of 29). Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors compared with preneoplastic tissues; in cell-intrinsic processes associated with mitosis, cell adhesion, and invasion; as well as in the surrounding tumor environment. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors that may model a subset of aggressive clinical ER+ breast cancers.

KEYWORDS:

ER+ breast cancer; Ras mutations; breast cancer; genomic analyses; mouse models; prolactin

PMID:
31390566
DOI:
10.1016/j.celrep.2019.06.098
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