Abstract
The proto-oncogene ErbB2 is known to be amplified and to play an important role in the development of about one-third of human breast cancers. Phosphatidylinositol 3-kinase (PI3K), which is often activated in ErbB2-overexpressing breast cancer cells, is known to regulate cell proliferation and cell survival. Selective inhibitors of the PI3K pathway were used to assess the relevance of PI3K signaling in the anchorage-independent growth of a series of human mammary carcinoma cell lines. Wortmannin, LY294002, and rapamycin at concentrations that did not affect MAPK phosphorylation but substantially inhibited PI3K, Akt, and p70S6K significantly suppressed the soft agar growth of tumor cell lines that overexpress ErbB2 but not the growth of tumor lines with low ErbB2 expression. A similar growth inhibition of ErbB2-overexpressing carcinoma lines was observed when a dominant negative p85PI3K mutant was introduced into these cells. Forced expression of ErbB2 in breast cancer lines originally expressing low ErbB2 levels augmented receptor expression and sensitized those lines to LY294002- and rapamycin-mediated inhibition of colony formation. Furthermore, treatment with LY294002 resulted in the selective increase of cyclin-dependent kinase inhibitors p21Cip1 or p27Kip1 and suppression of cyclin E-associated Cdk2 kinase activity in ErbB2-overexpressing lines, which may account for their hypersensitivity toward inhibitors of the PI3K pathway in anchorage-independent growth. Our results indicate that the PI3K/Akt/p70S6K pathway plays an enhanced role in the anchorage-independent growth of ErbB2-overexpressing breast cancer cells, therefore providing a molecular basis for the selective targeting of this signaling pathway in the treatment of ErbB2-related human breast malignancies.
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Abbreviations
- EGFR:
-
epidermal growth factor receptor
- PI3K:
-
phosphatidylinositol 3-kinase
- RPTK:
-
receptor protein tyrosine kinase
- MAPK:
-
mitogen activated protein kinase
- PKB:
-
protein kinase B
- Cdk:
-
cyclin-dependent kinase
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Acknowledgements
We are grateful to Dr Mien-Chie Hung (M. D. Anderson Cancer Center, Houston, TX, USA) for providing the ErbB2 expression plasmid and Dr Julian Downward (Imperial Cancer Research Fund, London, UK) for providing the Δp85 plasmid. This work was supported by National Institute of Health grants CA29339 and CA55054. U Hermanto was supported in part by Department of Defense Breast Cancer Predoctoral Training Program Grant DAMD 17-94-J-4111 and the Mount Sinai School of Medicine Medical Scientist Training Program, National Institute of General Medical Sciences Grant T32GM07280.
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Hermanto, U., Zong, C. & Wang, LH. ErbB2-overexpressing human mammary carcinoma cells display an increased requirement for the phosphatidylinositol 3-kinase signaling pathway in anchorage-independent growth. Oncogene 20, 7551–7562 (2001). https://doi.org/10.1038/sj.onc.1204964
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DOI: https://doi.org/10.1038/sj.onc.1204964
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