PT  - JOURNAL ARTICLE
AU  - Katie M. Campbell
AU  - Kathleen A. O’Leary
AU  - Debra E. Rugowski
AU  - William A. Mulligan
AU  - Erica K. Barnell
AU  - Zachary L. Skidmore
AU  - Kilannin Krysiak
AU  - Malachi Griffith
AU  - Linda A. Schuler
AU  - Obi L. Griffith
TI  - Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation
AID  - 10.1101/442624
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 442624
4099  - http://biorxiv.org/content/early/2018/10/16/442624.short
4100  - http://biorxiv.org/content/early/2018/10/16/442624.full
AB  - The 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.