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Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

Oncogene volume 25, pages 3408–3423 (2006)Cite this article

Abstract

We have examined the effects of transforming growth factor-beta (TGFβ) signaling on mammary epithelial cell survival. Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5T204D) exhibited reduced apoptosis in terminal endbuds and during postlactational involution. Transgene-expressing mammary cells contained lower Smad2/3 and higher c-myc levels than controls, high ligand-independent phosphatidylinositol-3 kinase (PI3K) and Akt activities, and were insensitive to TGFβ-mediated growth arrest. Treatment with a proteasome inhibitor increased Smad2/3 levels and ligand-independent Smad transcriptional reporter activity, as well as reduced both c-myc protein and basal cell proliferation. Treatment with an Alk5 kinase small-molecule inhibitor upregulated Smad2/3 levels, reduced PI3K activity, P-Akt, and c-myc, and inhibited cell survival. Although Alk5T204D-expressing mice did not develop mammary tumors, bigenic MMTV-AlkT204D × Neu mice developed cancers that were more metastatic than those occurring in MMTV-Neu transgenics. These data suggest that (1) TGFβ can signal to PI3K/Akt and enhance mammary epithelial cell survival in vivo before cytological or histological evidence of transformation, and (2) TGFβ signaling can provide epithelial cells with a ‘gain-of-function’ effect that synergizes with oncogene-induced transformation.

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Acknowledgements

This work was supported by NIH R01 grants CA62212 and CA80195 (CLA), AG022413 (MHB-H), Breast Cancer Specialized Program of Research Excellence (SPORE) Grant P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485. RZ is supported by a Veterans Administration Advanced Career Development and Merit Awards, the American Heart Association Grant in Aid Award, R01 DK069921, and a Clinician Scientist award from the National Kidney Foundation.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University school of Medicine, Nashville, 37232-6307, TN, USA

    R S Muraoka-Cook, I Shin, E Easterly, R Zent & C L Arteaga

  2. Department of Medicine, Vanderbilt University school of Medicine, Nashville, 37232-6307, TN, USA

    J Y Yi, R Zent & C L Arteaga

  3. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, 94720, CA, USA

    M H Barcellos-Hoff

  4. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, IN, USA

    J M Yingling

  5. Department of Research Medicine, Veterans Affairs Hospital, Nashville, 37232, TN, USA

    R Zent

  6. Vanderbilt-Ingram Cancer Center Breast Cancer Research Program Vanderbilt University school of Medicine, Nashville, 37232-6307, TN, USA

    C L Arteaga

  7. Department of Life Sciences, Hanyang University, Seoul, South Korea

    I Shin

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  1. R S Muraoka-Cook
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Correspondence to C L Arteaga.

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Muraoka-Cook, R., Shin, I., Yi, J. et al. Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25, 3408–3423 (2006). https://doi.org/10.1038/sj.onc.1208964

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