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

Cell Reports
Katie M CampbellObi L Griffith

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.

Citations

Mar 27, 2020·Medical Sciences : Open Access Journal·Ugo TestaElvira Pelosi
May 29, 2020·PLoS Genetics·Christina RossKent Hunter
May 16, 2020·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·C Zhang, R A Kurt
Mar 28, 2021·NPJ Breast Cancer·Jacqueline M GribleCharles V Clevenger
Oct 29, 2020·Seminars in Cell & Developmental Biology·Ödül Karayazi AtıcıCarrie S Shemanko

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