The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor

Abstract

The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-Early^Ex and Wnt1-Late^Ex Here, we extend this initial observation and show that Wnt1-Early^Ex tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-Early^Ex tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-Early^Ex tumors had primarily Cd49f^pos/Epcam^neg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-Late^Ex tumors had a bloody gross pathology, which was highlighted by the presence of 'blood lakes' identified by H&E staining. These tumors had primarily Cd49f^pos/Epcam^pos FACS profiles, but also contained a secondary Cd49f^pos/Epcam^neg subpopulation. Wnt1-Late^Ex tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor.

Keywords: Breast cancer; EGFR inhibitor; Genetically engineered mouse model; MMTV-Wnt1.