Breast Cancer Bone Metastasis Mediated by the Smad Tumor Suppressor Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Sep 21

PMID 16172383

Citations 263

Authors

Yibin Kang

Wei He

Shaun Tulley

Gaorav P Gupta

Inna Serganova

Chang-Rung Chen

Katia Manova-Todorova

Ronald Blasberg

William L Gerald

Joan Massague

Affiliations

Soon will be listed here.

Abstract

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.

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References

Kakonen S, Selander K, Chirgwin J, Yin J, Burns S, Rankin W . Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem. 2002; 277(27):24571-8. DOI: 10.1074/jbc.M202561200. View

Campbell R, Tour O, Palmer A, Steinbach P, Baird G, Zacharias D . A monomeric red fluorescent protein. Proc Natl Acad Sci U S A. 2002; 99(12):7877-82. PMC: 122988. DOI: 10.1073/pnas.082243699. View

Mundy G . Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002; 2(8):584-93. DOI: 10.1038/nrc867. View

Takeuchi Y, Watanabe S, Ishii G, Takeda S, Nakayama K, Fukumoto S . Interleukin-11 as a stimulatory factor for bone formation prevents bone loss with advancing age in mice. J Biol Chem. 2002; 277(50):49011-8. DOI: 10.1074/jbc.M207804200. View

Kang Y, Chen C, Massague J . A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003; 11(4):915-26. DOI: 10.1016/s1097-2765(03)00109-6. View

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

Dumont N, Arteaga C . Targeting the TGF beta signaling network in human neoplasia. Cancer Cell. 2003; 3(6):531-6. DOI: 10.1016/s1535-6108(03)00135-1. View

Kang Y, Siegel P, Shu W, Drobnjak M, Kakonen S, Cordon-Cardo C . A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003; 3(6):537-49. DOI: 10.1016/s1535-6108(03)00132-6. View

Siegel P, Shu W, Cardiff R, Muller W, Massague J . Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A. 2003; 100(14):8430-5. PMC: 166246. DOI: 10.1073/pnas.0932636100. View

10.

Bamba S, Andoh A, Yasui H, Makino J, Kim S, Fujiyama Y . Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways. Am J Physiol Gastrointest Liver Physiol. 2003; 285(3):G529-38. DOI: 10.1152/ajpgi.00050.2003. View

11.

Eferl R, Wagner E . AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003; 3(11):859-68. DOI: 10.1038/nrc1209. View

12.

Tian F, Dacosta Byfield S, Parks W, Yoo S, Felici A, Tang B . Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res. 2003; 63(23):8284-92. View

13.

Siegel P, Massague J . Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003; 3(11):807-21. DOI: 10.1038/nrc1208. View

14.

Morgan H, Tumber A, Hill P . Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J Cancer. 2004; 109(5):653-60. DOI: 10.1002/ijc.20056. View

15.

Ponomarev V, Doubrovin M, Serganova I, Vider J, Shavrin A, Beresten T . A novel triple-modality reporter gene for whole-body fluorescent, bioluminescent, and nuclear noninvasive imaging. Eur J Nucl Med Mol Imaging. 2004; 31(5):740-51. DOI: 10.1007/s00259-003-1441-5. View

16.

Tian F, Dacosta Byfield S, Parks W, Stuelten C, Nemani D, Zhang Y . Smad-binding defective mutant of transforming growth factor beta type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res. 2004; 64(13):4523-30. DOI: 10.1158/0008-5472.CAN-04-0030. View

17.

Serganova I, Doubrovin M, Vider J, Ponomarev V, Soghomonyan S, Beresten T . Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice. Cancer Res. 2004; 64(17):6101-8. DOI: 10.1158/0008-5472.CAN-04-0842. View

18.

CAILLEAU R, Young R, Olive M, REEVES Jr W . Breast tumor cell lines from pleural effusions. J Natl Cancer Inst. 1974; 53(3):661-74. PMC: 7364228. DOI: 10.1093/jnci/53.3.661. View

19.

Girasole G, Passeri G, Jilka R, Manolagas S . Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest. 1994; 93(4):1516-24. PMC: 294166. DOI: 10.1172/JCI117130. View

20.

Schutte M, Hruban R, Hedrick L, Cho K, Nadasdy G, Weinstein C . DPC4 gene in various tumor types. Cancer Res. 1996; 56(11):2527-30. View