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

Katie M. Campbell, Kathleen A. O'Leary, Debra E. Rugowski, William A. Mulligan, Erica K. Barnell, Zachary L. Skidmore, Kilannin Krysiak, Malachi Griffith, Linda A. Schuler, O. L. Griffith

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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. Campbell et al. identify highly recurrent Kras-activating mutations in spontaneous prolactin-induced ER+ mammary tumors in female mice. This mimics the association between elevated prolactin and risk of ER+ breast cancer in postmenopausal women, providing a useful model for an important subset of aggressive clinical ER+ breast cancers.

Original languageEnglish
Pages (from-to)1526-1537.e4
JournalCell Reports
Volume28
Issue number6
DOIs
StatePublished - Aug 6 2019

Keywords

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

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    Campbell, K. M., O'Leary, K. A., Rugowski, D. E., Mulligan, W. A., Barnell, E. K., Skidmore, Z. L., Krysiak, K., Griffith, M., Schuler, L. A., & Griffith, O. L. (2019). A Spontaneous Aggressive ERα+ Mammary Tumor Model Is Driven by Kras Activation. Cell Reports, 28(6), 1526-1537.e4. https://doi.org/10.1016/j.celrep.2019.06.098