Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells

Abstract

It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared to the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of TGFβ/SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal-luminal crosstalk in normal mammary tissue.

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…68 Concordantly, other studies showed that Wnt5a may suppress breast cancer progression and loss of its expression is associated with poor prognosis. [67][68][69][70][71][72][73][74] On the contrary, reports also demonstrated a positive role of Wnt5a in promoting tumor growth and migration in TNBC. [75][76][77] The observed paradoxical effects of Wnt5a may be dependent upon its signaling context, leading to controversy over its role in breast cancer tumorigenesis and metastasis.…”

Paracrine WNT5A signaling in healthy and neoplastic mammary tissue

“…10 We found that Tgfb and Wnt5a form a feed-forward activating mechanism whereby Tgfb induces Wnt5a expression in mammary epithelium, likely from luminal cells. Wnt5a, in turn, leads to the activation of Smad2 in Erbb2-expressing basal mammary epithelial cells (referred to as basal tumor-initiating cells, or basal TIC Fig.…”

Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling

“…We further distinguished the activities of these two WNTs in mammosphere assays by demonstrating that WNT5A enhances mammosphere formation through the RYK receptor. This stimulatory activity is surprising in light of studies on human tumors that showed tumor-suppressive activity of WNT5A, with loss of Wnt5a expression correlating with more aggressive tumor subtypes, earlier relapse, and significantly shorter overall patient survival (26,27). WNT5A was shown to induce the formation of a RYK/TGFβR1 complex in MCF10A cells and activate SMAD2 in mammary epithelial cells harvested from preneoplastic MMTV-ErbB2/Wnt5a +/− mice (27).…”