Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: Possibilities for therapeutic intervention

Nicole M. Davis, Melissa Sokolosky, Kristin Stadelman, Steve L. Abrams, Massimo Libra, Saverio Candido, Ferdinando Nicoletti, Jerry Polesel, Roberta Maestro, Antonio D'Assoro, Lyudmyla Drobot, Dariusz Rakus, Agnieszka Gizak, Piotr Laidler, Joanna Dulinska-Litewka, Joerg Basecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Giuseppe Montalto, Melchiorre CervelloTimothy L. Fitzgerald, Zoya N. Demidenko, Alberto M. Martelli, Lucio Cocco, Linda S. Steelman, James A. McCubrey

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.

Original languageEnglish (US)
Pages (from-to)4603-4650
Number of pages48
JournalOncotarget
Volume5
Issue number13
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Keywords

  • MTOR
  • Mutations
  • PI3K
  • Rapamycin
  • Targeted therapy
  • Therapy resistance

ASJC Scopus subject areas

  • Oncology

Cite this

Davis, N. M., Sokolosky, M., Stadelman, K., Abrams, S. L., Libra, M., Candido, S., Nicoletti, F., Polesel, J., Maestro, R., D'Assoro, A., Drobot, L., Rakus, D., Gizak, A., Laidler, P., Dulinska-Litewka, J., Basecke, J., Mijatovic, S., Maksimovic-Ivanic, D., Montalto, G., ... McCubrey, J. A. (2014). Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: Possibilities for therapeutic intervention. Oncotarget, 5(13), 4603-4650. https://doi.org/10.18632/oncotarget.2209