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Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor β1
Open accessAbstract
To determine if Neu is dominant over transforming growth factor beta (TGF-beta), we crossed mouse mammary tumor virus (MMTV)-Neu mice with MMTV-TGF-beta1(S223/225) mice expressing active TGF-beta1 in the mammary gland. Bigenic (NT) and Neu-induced mammary tumors developed with a similar latency. The bigenic tumors and their metastases were less proliferative than those occurring in MMTV-Neu mice. However, NT tumors exhibited less apoptosis and were more locally invasive and of higher histological grade. NT mice exhibited more circulating tumor cells and lung metastases than Neu mice, while NT tumors contained higher levels of phosphorylated (active) Smad2, Akt, mitogen-activated protein kinase (MAPK), and p38, as well as vimentin content and Rac1 activity in situ than tumors expressing Neu alone. Ex vivo, NT cells exhibited higher levels of P-Akt and P-MAPK than Neu cells. These were inhibited by the TGF-beta inhibitor-soluble TGF-beta type II receptor (TbetaRII:Fc), suggesting they were activated by autocrine TGF-beta. TGF-beta stimulated migration of Neu cells into surrounding matrix, while the soluble TGF-beta inhibitor abrogated motility and invasiveness of NT cells. These data suggest that (i) the antimitogenic and prometastatic effects of TGF-beta can exist simultaneously and (ii) Neu does not abrogate TGF-beta-mediated antiproliferative action but can synergize with TGF-beta in accelerating metastatic tumor progression.
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Cites
Missing Pieces in the NF-κB Puzzle
Ghosh, S., & Karin, M. (2002) · Cell · doi:10.1016/s0092-8674(02)00703-1 · Cited by 3,638
TGF-β Signaling in Tumor Suppression and Cancer Progression
Derynck, R., Akhurst, R. J., & Balmain, A. (2001) · Nature Genetics · doi:10.1038/ng1001-117 · Cited by 2,275
Cited by
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907
Signaling cross-talk between TGF-β/BMP and other pathways
Guo, X., & Wang, X.-F. (2009) · Cell Research · doi:10.1038/cr.2008.302 · Cited by 1,015
Modelling glandular epithelial cancers in three-dimensional cultures
Debnath, J., & Brugge, J. S. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1695 · Cited by 1,015
Yang, L., Huang, J., Ren, X., Gorska, A. E., Chytil, A., Aakre, M., Carbone, D. P., Matrisian, L. M., Richmond, A., Lin, P. C., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.12.004 · Cited by 918
Self-citationMacKeigan, J. P., Murphy, L. O., & Blenis, J. (2005) · Nature Cell Biology · doi:10.1038/ncb1258 · Cited by 561
Metadata
- Authors
- Muraoka, R. S., Koh, Y., Roebuck, L. R., Sanders, M. E., Brantley-Sieders, D., Gorska, A. E., Moses, H. L., & Arteaga, C. L.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-12-01
- Volume
- 23
- Issue
- 23
- Pages
- 8691-8703
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2163032998
- Cited by
- 191
- References
- 2
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- green
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- Muraoka, R. S., Koh, Y., Roebuck, L. R., Sanders, M. E., Brantley-Sieders, D., Gorska, A. E., Moses, H. L., & Arteaga, C. L. (2003). Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor β1. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.23.23.8691-8703.2003
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