Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway.
TGF-beta can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-beta while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bone-metastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.
Kang
Yibin
Y
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Molecular Cytology Laboratory, Memorial Sloan-Kettering Cancer Center, NY 10021, USA.
He
Wei
W
Tulley
Shaun
S
Gupta
Gaorav P
GP
Serganova
Inna
I
Chen
Chang-Rung
CR
Manova-Todorova
Katia
K
Blasberg
Ronald
R
Gerald
William L
WL
Massagué
Joan
J
D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D017370:Interleukin-11; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins