Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway Journal Article
| Authors: | Kang, Y.; He, W.; Tulley, S.; Gupta, G. P.; Serganova, I.; Chen, C. R.; Manova-Todorova, K.; Blasberg, R.; Gerald, W. L.; Massague, J. |
| Article Title: | Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway |
| Abstract: | TGF-β 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-β 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. © 2005 by The National Academy of Sciences of the USA. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; bone neoplasms; osteolysis; gene mutation; bone metastasis; protein function; cell proliferation; animals; mice; breast cancer; smad protein; transforming growth factor beta; transcription factor; tumor xenograft; breast neoplasms; cancer inhibition; oncogene; gene expression regulation, neoplastic; molecular sequence data; tumor suppressor proteins; base sequence; neoplasm transplantation; tumor growth; tumor suppressor protein; cytostasis; transcription factor ap 1; tgf-β; promoter regions (genetics); interleukin-11; trans-activation (genetics); il-11; smad4; il 11 gene |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 102 |
| Issue: | 39 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2005-09-01 |
| Start Page: | 13909 |
| End Page: | 13914 |
| Language: | English |
| DOI: | 10.1073/pnas.0506517102 |
| PUBMED: | 16172383 |
| PROVIDER: | scopus |
| PMCID: | PMC1236573 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 191" - "Export Date: 24 October 2012" - "CODEN: PNASA" - "Source: Scopus" |
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