A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer.
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.
DiMeo
Theresa A
TA
Department of Anatomy and Cellular Biology, Sackler School, Tufts University School of Medicine, Boston, MA 02111, USA.
Anderson
Kristen
K
Phadke
Pushkar
P
Fan
Cheng
C
Feng
Chang
C
Perou
Charles M
CM
Naber
Steven
S
Kuperwasser
Charlotte
C
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary*; D008648:Mesoderm / Q000166:cytology / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology*
D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051153:Wnt Proteins