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

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.

SUBMITTER: Campbell KM 

PROVIDER: S-EPMC6713291 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature