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

Oncogene volume 30, pages 301–312 (2011)Cite this article

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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.

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Acknowledgements

We thank Dr Mina Bissell, Lawrence Berkley National Laboratory for the gift of casein antibody, and Robert Abraham, Pfizer Research for his interest and support of the project. This work was supported by a collaborative research grant from Pfizer Research, and shared resource support from the NCI Cancer Center Support Grant 2 P30 CA030199 and R01 CA125255 (MK).

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Author notes

  1. L Hebbard

    Present address: 9Current address: Westmead Millennium Institute, Storr Liver Unit, Westmead NSW 2145, Australia.,

  2. L Hebbard, G Cecena, J Sawada, A Charbono, R Williams, M Wankell, M Komatsu and R G Oshima: Formerly Burnham Institute for Medical Research.

  3. J Golas, K T Arndt, S Q DeJoy, R A Rollins, V Diesl, M Follettie, L Chen, E Rosfjord and F Boschelli: Formerly Wyeth Oncology Discovery Research.

Authors and Affiliations

  1. Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    L Hebbard, G Cecena, A Charbono, R Williams, M Wankell & R G Oshima

  2. Center for Integrative Biology and Biotherapeutics, Pfizer Research, Pearl River, NY, USA

    J Golas, K T Arndt, S Q DeJoy, R A Rollins, V Diesl, M Follettie, L Chen, E Rosfjord & F Boschelli

  3. Sanford-Burnham Medical Research Institute, Lake Nona, FL, USA

    J Sawada & M Komatsu

  4. Pathology Department, University of California, San Diego, CA, USA,

    L G Ellies

  5. Biomedical Science Program, University of California, San Diego, La Jolla, CA, USA

    R E Jimenez

  6. Center for Genomic Pathology University of California, Davis, CA, USA

    R D Cardiff

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Correspondence to R G Oshima.

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Competing interests

Kim Arndt, Frank Boschelli, Lei Chen, Susan Q DeJoy, Veronica Diesl, Maxmillian Follettie, Jonathan Golas, Robert Rollins and Edward Rosfjord are employees of Pfizer (formerly Wyeth Research), which is pursuing clinical development of bosutinib. All the remaining authors declare no conflict of interest.

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Hebbard, L., Cecena, G., Golas, J. et al. Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene 30, 301–312 (2011). https://doi.org/10.1038/onc.2010.412

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