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

Cell Rep. 2019 Aug 6;28(6):1526-1537.e4. doi: 10.1016/j.celrep.2019.06.098.


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.

Keywords: ER+ breast cancer; Ras mutations; breast cancer; genomic analyses; mouse models; prolactin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Carcinogenesis / genetics
  • Datasets as Topic
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Profiling
  • Humans
  • Mammary Neoplasms, Experimental / etiology*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Prolactin / genetics
  • Prolactin / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Rats
  • Signal Transduction
  • Transgenes


  • Estrogen Receptor alpha
  • KRAS protein, human
  • Kras protein, rat
  • Prolactin
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)