TGFβ-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential.

Abstract

We have delineated TGFβ signaling pathways in the production of osteolytic factors interleukin-8 and interleukin-11 in breast cancer cells with different bone metastases potential. Bone seeking MDA-MB-231(hm) cells expressed higher levels of IL-11, but lower levels of IL-8 compared to MDA-MB-231 cells. MCF-7 cells (mainly osteoblastic) did not express IL-8 or IL-11; MDA-MB-468 cells (weakly metastatic) expressed IL-8, but not IL-11. The up-regulation of IL-11 and IL-8 was associated with the rapid activation of SMAD2/3 and p38 MAPK through the TGFβ/TGFβR system. Analysis of TGFβ receptors indicated that MCF-7 cells do not express TGFβRII, and MDA-MB-468 cells do not express SMAD4. Inactivation of SMAD4 or p38PMAPK gene via RNAi resulted in the inhibition of IL-11 and IL-8 production in MDA-MB-231(hm) cells; and over-expression of SMAD4 gene resulted in IL-11 production in MDA-MB-468 cells. TGFβ-1 induced SMAD3 translocation to the nuclei in MDA-MB-231, MDA-MB-231(hm) as well as in SMAD4 deficient MDA-MB-468, indicating that an alternate non-canonical pathway could be responsible for TGFβ-1 induced cytokine production in MDA-MB-468 cells. Thus, four breast cancer cell lines used in this study show differential expression and up-regulation of the osteolytic factors in response to TGFβ-1 that involves both SMAD pathway, a non-canonical SMAD pathway, as well as p38 MAPK pathways.

• Authors: Janhavi Gupta, John Robbins, Tamas Jilling, Prem Seth
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 11 Issue 3 Pg. 311-6 (Feb 01 2011) ISSN: 1555-8576 [Electronic] United States
• PMID: 21099351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-11
• Interleukin-8
• RNA, Small Interfering
• Receptors, Transforming Growth Factor beta
• Smad Proteins
• Transforming Growth Factor beta
• p38 Mitogen-Activated Protein Kinases

Topics

• Bone Neoplasms (secondary)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Interleukin-11 (genetics, metabolism)
• Interleukin-8 (genetics, metabolism)
• Neoplasm Metastasis
• RNA, Small Interfering
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction
• Smad Proteins (genetics, metabolism)
• Transforming Growth Factor beta (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)