TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development

Juan Juan Yin, Katri Selander, John Chirgwin, Mark Dallas, Barry G. Grubbs, Rotraud Wieser, Joan Massagué, Gregory R. Mundy, Theresa Guise

Research output: Contribution to journalArticle

716 Citations (Scopus)

Abstract

Breast cancer frequently metastasizes to the skeleton, and the associated bone destruction is mediated by the osteoclast. Growth factors, including transforming growth factor-β (TGF-β), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-β inhibits growth of epithelial cells, and carcinoma cells are often defective in TGF-β responses, any role of TGF-β in metastasis is likely to be mediated by effects on the surrounding normal tissue. However, we present evidence that TGF-β promotes breast cancer metastasis by acting directly on the tumor cells. Expression of a dominant-negative mutant (TβRIIΔcyt) of the TGF-β type II receptor rendered the human breast cancer cell line MDA- MB-231 unresponsive to TGF-β. In a murine model of bone metastases, expression of TβRIIΔcyt by MDA-MB-231 resulted in less bone destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant-negative signaling blockade by expression of a constitutively active TGF-β type I receptor in the breast cancer cells increased tumor production of parathyroid hormone-related protein (PTHrP), enhanced osteolytic bone metastasis, and decreased survival. Transfection of MDA-MB-231 cells that expressed the dominant-negative TβRIIΔ-cyt with the cDNA for PTHrP resulted in constitutive tumor PTHrP production and accelerated bone metastases. These data demonstrate an important role for TGF-β in the development of breast cancer metastasis to bone, via the TGF-β receptor-mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalJournal of Clinical Investigation
Volume103
Issue number2
StatePublished - Jan 1999
Externally publishedYes

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Parathyroid Hormone-Related Protein
Bone Neoplasms
Bone Development
Transforming Growth Factors
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Growth Factor Receptors
Osteoclasts
Neoplasms
Bone Matrix
Survival
Growth
Skeleton
Transfection
Intercellular Signaling Peptides and Proteins
Complementary DNA
Epithelial Cells
Carcinoma

ASJC Scopus subject areas

  • Medicine(all)

Cite this

TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. / Yin, Juan Juan; Selander, Katri; Chirgwin, John; Dallas, Mark; Grubbs, Barry G.; Wieser, Rotraud; Massagué, Joan; Mundy, Gregory R.; Guise, Theresa.

In: Journal of Clinical Investigation, Vol. 103, No. 2, 01.1999, p. 197-206.

Research output: Contribution to journalArticle

Yin, JJ, Selander, K, Chirgwin, J, Dallas, M, Grubbs, BG, Wieser, R, Massagué, J, Mundy, GR & Guise, T 1999, 'TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development', Journal of Clinical Investigation, vol. 103, no. 2, pp. 197-206.
Yin, Juan Juan ; Selander, Katri ; Chirgwin, John ; Dallas, Mark ; Grubbs, Barry G. ; Wieser, Rotraud ; Massagué, Joan ; Mundy, Gregory R. ; Guise, Theresa. / TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 2. pp. 197-206.
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