| First Author | Pfefferle AD | Year | 2019 |
| Journal | Dis Model Mech | Volume | 12 |
| Issue | 7 | PubMed ID | 31213486 |
| Mgi Jnum | J:278072 | Mgi Id | MGI:6356141 |
| Doi | 10.1242/dmm.037192 | Citation | Pfefferle AD, et al. (2019) The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor. Dis Model Mech 12(7):dmm037192 |
| abstractText | 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. |
