The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.
Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases TGF-beta signaling in human breast cancer cells and induces an epithelial-mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Accordingly, we used spontaneous and experimental metastasis mouse models to demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 correlated with nuclear Smad3 and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpressed Six1 had a shortened time to relapse and metastasis and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlated with adverse outcomes in numerous other cancers including brain, cervical, prostate, colon, kidney, and liver. Our findings indicate that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.
Micalizzi
Douglas S
DS
Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Christensen
Kimberly L
KL
Jedlicka
Paul
P
Coletta
Ricardo D
RD
Barón
Anna E
AE
Harrell
J Chuck
JC
Horwitz
Kathryn B
KB
Billheimer
Dean
D
Heichman
Karen A
KA
Welm
Alana L
AL
Schiemann
William P
WP
Ford
Heide L
HL
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004848:Epithelium / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology; D009368:Neoplasm Transplantation; D011379:Prognosis; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014183:Transplantation, Heterologous
D018398:Homeodomain Proteins; C099236:SIX1 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta