Abstract
ABSTRACTThe 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-EarlyEx and Wnt1-LateEx. Here, we extend this initial observation and show that Wnt1-EarlyEx tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors had primarily Cd49fpos/Epcamneg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-LateEx tumors had a bloody gross pathology, which was highlighted by the presence of ‘blood lakes’ identified by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx 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.
Highlights
The mammalian breast is a unique organ capable of dynamic morphological and physiological change during organogenesis, puberty, pregnancy, lactation and involution (Gjorevski and Nelson, 2011)
The basal layer is enriched for myoepithelial cells and mammary stem cells (MaSC) (Woodward et al, 2005) and the luminal layer contains a combination of estrogen receptor (ER)-positive and ER-negative mature luminal cells (Visvader, 2009)
No differences were observed on a DNA copy number level between early versus late tumors (Fig. S2), gene expression profiling found that these Wnt-EarlyEx and Wnt1-LateEx tumors have distinct expression and pathological features (Pfefferle et al, 2013) (Fig. 1B)
Summary
The mammalian breast is a unique organ capable of dynamic morphological and physiological change during organogenesis, puberty, pregnancy, lactation and involution (Gjorevski and Nelson, 2011). The basal layer is enriched for myoepithelial cells and mammary stem cells (MaSC) (Woodward et al, 2005) and the luminal layer contains a combination of estrogen receptor (ER)-positive and ER-negative mature luminal cells (Visvader, 2009) Each cell within this hierarchy has developed specialized functions to support the necessary changes that will occur over a woman’s lifetime. The other Wntregulated pathways are collectively referred to as non-canonical Wnt signaling These include calcium and planar cell polarity signaling through Fzd receptors, Jnk signaling through the Ror receptor and Src signaling through the Ryk receptor (Roarty and Rosen, 2010). Given the importance of Wnt signaling for controlling cell growth, differentiation and stem cell self-renewal (Anastas and Moon, 2013), a research emphasis has been placed on better understanding these Wnt signaling pathways
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