Control of mammary tumor differentiation by SKI-606 (bosutinib)

L. Hebbard, G. Cecena, J. Golas, Junko Sawada, L. G. Ellies, A. Charbono, R. Williams, R. E. Jimenez, M. Wankell, K. T. Arndt, S. Q. Dejoy, R. A. Rollins, V. Diesl, M. Follettie, L. Chen, E. Rosfjord, R. D. Cardiff, Masanobu Komatsu, F. Boschelli, R. G. Oshima

Research output: Contribution to journalArticle

Abstract

C-Src is infrequently mutated in human cancers but it mediates oncogenic signals of many activated growth factor receptors and thus remains a key target for cancer therapy. However, the broad function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune-competent environment. In an effort to understand the appropriate clinical use of Src inhibitors, we tested an Src inhibitor, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model that permits assessment of effects on different stages of tumor progression. Here we show that oral administration of SKI-606 inhibited the phosphorylation of Src in mammary tumors and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in over 50% of the animals and stopped tumor growth in older animals with pre-existing tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors by inducing differentiation.

Original languageEnglish (US)
Pages (from-to)301-312
Number of pages12
JournalOncogene
Volume30
Issue number3
DOIs
StatePublished - Jan 20 2011
Externally publishedYes

Fingerprint

Breast Neoplasms
Neoplasms
Vascular Tissue Neoplasms
bosutinib
Growth Factor Receptors
src-Family Kinases
Transgenic Mice
Oral Administration
Phosphorylation
Cell Proliferation
Therapeutics
Growth

Keywords

  • breast cancer
  • Ezh2
  • mouse
  • SKI-606
  • Src

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Hebbard, L., Cecena, G., Golas, J., Sawada, J., Ellies, L. G., Charbono, A., ... Oshima, R. G. (2011). Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene, 30(3), 301-312. https://doi.org/10.1038/onc.2010.412

Control of mammary tumor differentiation by SKI-606 (bosutinib). / Hebbard, L.; Cecena, G.; Golas, J.; Sawada, Junko; Ellies, L. G.; Charbono, A.; Williams, R.; Jimenez, R. E.; Wankell, M.; Arndt, K. T.; Dejoy, S. Q.; Rollins, R. A.; Diesl, V.; Follettie, M.; Chen, L.; Rosfjord, E.; Cardiff, R. D.; Komatsu, Masanobu; Boschelli, F.; Oshima, R. G.

In: Oncogene, Vol. 30, No. 3, 20.01.2011, p. 301-312.

Research output: Contribution to journalArticle

Hebbard, L, Cecena, G, Golas, J, Sawada, J, Ellies, LG, Charbono, A, Williams, R, Jimenez, RE, Wankell, M, Arndt, KT, Dejoy, SQ, Rollins, RA, Diesl, V, Follettie, M, Chen, L, Rosfjord, E, Cardiff, RD, Komatsu, M, Boschelli, F & Oshima, RG 2011, 'Control of mammary tumor differentiation by SKI-606 (bosutinib)', Oncogene, vol. 30, no. 3, pp. 301-312. https://doi.org/10.1038/onc.2010.412
Hebbard L, Cecena G, Golas J, Sawada J, Ellies LG, Charbono A et al. Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene. 2011 Jan 20;30(3):301-312. https://doi.org/10.1038/onc.2010.412
Hebbard, L. ; Cecena, G. ; Golas, J. ; Sawada, Junko ; Ellies, L. G. ; Charbono, A. ; Williams, R. ; Jimenez, R. E. ; Wankell, M. ; Arndt, K. T. ; Dejoy, S. Q. ; Rollins, R. A. ; Diesl, V. ; Follettie, M. ; Chen, L. ; Rosfjord, E. ; Cardiff, R. D. ; Komatsu, Masanobu ; Boschelli, F. ; Oshima, R. G. / Control of mammary tumor differentiation by SKI-606 (bosutinib). In: Oncogene. 2011 ; Vol. 30, No. 3. pp. 301-312.
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