Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Author:

Campbell Katie M.ORCID,O’Leary Kathleen A.,Rugowski Debra E.,Mulligan William A.,Barnell Erica K.ORCID,Skidmore Zachary L.ORCID,Krysiak KilanninORCID,Griffith MalachiORCID,Schuler Linda A.ORCID,Griffith Obi L.ORCID

Abstract

SummaryThe NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors, 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% (23/29) of tumors. Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors, compared to preneoplastic tissues, in cell-intrinsic processes associated with mitosis, cell adhesion and invasion, as well as in the tumor microenvironment, including immune activity. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors which may model a subset of aggressive clinical ER+ breast cancers.

Publisher

Cold Spring Harbor Laboratory

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