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

Abstract

SUMMARY 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.

The genomic landscape of metastasis in treatment-naïve breast cancer models

“…In 2001, D'Cruz et al described sustained oncogenic transformation following spontaneous mutagenesis of Kras2 in an inducible c-Myc mammary tumorigenesis model [59]. In 2019, Campbell et al reported spontaneous alterations in Kras expression and activity in the aggressive ERα + NRL-PRL postmenopausal murine model, that drove neoplastic transformation [60]. Additionally, the Kras Q61H mutation was identified in primary tumors from a triple negative murine model by Liu et.…”

The human intermediate prolactin receptor is a mammary proto-oncogene

“…1 ), suggest Ras may cooperate with hPRLrL+I heterodimers during transformation. Furthermore, recent studies with a transgenic PRL over-expression mouse model have implicated KRAS signaling involvement in PRL-dependent mammary neoplasias 6 , 26 . KRAS promotes metastatic dissemination, and therefore, is strongly correlated with worse overall patient outcome 27 .…”

“…KRAS holds a prominent cooperative role with hPRLr in breast cancer pathogenesis. For example, in characterizing a PRL-driven mammary cancer mouse line (NRL-PRL), genomic analyses uncovered consistent oncogenic KRAS somatic mutations/amplifications in all primary tumors, which was not found in pre-neoplastic glands 26 . These findings coincided with recent discoveries of significant KRAS involvement in breast cancer metastatic dissemination, mirroring the in vivo results presented herein 27 .…”

“…Accordingly, the approaches utilized in this study were able to successfully focus on those clinical features that associated with both 1) hPRLrI expression, and 2) the hPRLrI:hPRLrL ratio. While a handful of recent studies have suggested a role for this receptor in TNBC, PRL/hPRLr have traditionally been associated with luminal breast cancers, and this association is observed with only hPRLrL 6 , 26 , 29 . Interestingly, the clinical data presented here highlight a novel association between the hPRLrI isoform and aggressive TNBC/basal-like breast cancers, corroborating both the in vivo and in vitro studies presented herein.…”

Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

“…Sequencing data from genetically engineered mouse models is largely lacking, with only a few models having been sequenced 30 , 36 – 38 . SNV mutation rates between previous studies and ours indicate similarities, and small discrepancies may be explained through differences in data processing methods.…”