A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer

TLDR

Metastasis requires cancer cells to acquire a migratory phenotype and the ability to regenerate tumors in distant tissues, a process linked to EMT in basal‑like breast cancers that generates stem‑like cells facilitating dissemination. The study aims to define the molecular mechanisms linking stem‑cell–like traits with EMT in basal‑like breast cancer. An orthotopic human breast cancer lung metastasis model was used to identify a poor‑prognosis gene signature enriched for Wnt pathway components overexpressed in early lung metastases. The Wnt genes in the signature were strongly associated with human basal‑like breast cancers; inhibiting Wnt signaling via LRP6 reduced self‑renewal and tumor seeding, re‑expressed epithelial differentiation markers, and repressed EMT transcription factors SLUG and TWIST, linking self‑renewal, EMT, and metastasis. Cancer Res 2009;69(13):5364–73.

Abstract

Abstract The establishment of metastasis depends on the ability of cancer cells to acquire a migratory phenotype combined with their capacity to recreate a secondary tumor in a distant tissue. In epithelial cancers, such as those of the breast, the epithelial-mesenchymal transition (EMT) is associated with basal-like breast cancers, generates cells with stem-like properties, and enables cancer cell dissemination and metastasis. However, the molecular mechanism(s) that connects stem cell–like characteristics with EMT has yet to be defined. Using an orthotopic model of human breast cancer metastasis to lung, we identified a poor prognosis gene signature, in which several components of the wnt signaling pathway were overexpressed in early lung metastases. The wnt genes identified in this signature were strongly associated with human basal-like breast cancers. We found that inhibiting wnt signaling through LRP6 reduced the capacity of cancer cells to self-renew and seed tumors in vivo. Furthermore, inhibition of wnt signaling resulted in the reexpression of breast epithelial differentiation markers and repression of EMT transcription factors SLUG and TWIST. Collectively, these results provide a molecular link between self-renewal, EMT, and metastasis in basal-like breast cancers. [Cancer Res 2009;69(13):5364–73]