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PMID: 19727403 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment.

PloS one ·Vol. 4 ·No. 9 ·2009-09-03 ·Pages e6896

Dunn LK, Mohammad KS, Fournier PG, McKenna CR, Davis HW, Niewolna M, Peng XH, Chirgwin JM, Guise TA

Abstract

Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- beta. We asked whether hypoxia (via HIF-1alpha) and TGF-beta signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. We analyzed interactions between HIF-1alpha and TGF-beta pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-beta and hypoxia, with effects on the proximal promoters. We inhibited HIF-1alpha and TGF-beta pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. Hypoxia and TGF-beta signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1alpha and TGF-beta may improve treatment of bone metastases and increase survival.

MeSH Terms
Animals Bone Neoplasms/metabolism,secondary Bone and Bones/pathology Breast Neoplasms/metabolism,pathology Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Mice Neoplasm Metastasis Receptors, CXCR4/metabolism Signal Transduction Transforming Growth Factor beta/metabolism Vascular Endothelial Growth Factor A/metabolism
Chemicals
CXCR4 protein, human Hypoxia-Inducible Factor 1, alpha Subunit Receptors, CXCR4 Transforming Growth Factor beta Vascular Endothelial Growth Factor A
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Dunn Lauren K
Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
Mohammad Khalid S
Fournier Pierrick G J
McKenna C Ryan
Davis Holly W
Niewolna Maria
Peng Xiang Hong
Chirgwin John M
Guise Theresa A
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0006896
Published
2009-09-03
Epub
2009-00-03
Pages
e6896
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2731927
Subset
IM
Grants
NCI NIH HHS · R01 CA069158 · United States
NCI NIH HHS · PC040341 · United States
NCI NIH HHS · BC073157 · United States
NCI NIH HHS · PC061185 · United States
NIGMS NIH HHS · T32 GM007267 · United States
NIGMS NIH HHS · T32-GM007267 · United States
NCI NIH HHS · PC051194 · United States
NCI NIH HHS · T32-CA009109 · United States
NCI NIH HHS · T32 CA009109 · United States
NCI NIH HHS · R01-CA69158 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0006896 PMC Full Text View journal details
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