Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification

J. Tanizaki, Isamu Okamoto, S. Fumita, W. Okamoto, K. Nishio, K. Nakagawa

Research output: Contribution to journalArticle

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Abstract

Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this anti-tumor action has remained unclear, however. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. Lapatinib induced apoptosis in association with upregulation of the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference (RNAi)-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The pro-apoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited pro-apoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNAi or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification.

Original languageEnglish
Pages (from-to)4097-4106
Number of pages10
JournalOncogene
Volume30
Issue number39
DOIs
Publication statusPublished - Sep 29 2011
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Down-Regulation
Apoptosis
Breast Neoplasms
Mutation
MAP Kinase Signaling System
RNA Interference
Apoptosis Regulatory Proteins
human ERBB2 protein
lapatinib
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Catalytic Domain
Up-Regulation
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification. / Tanizaki, J.; Okamoto, Isamu; Fumita, S.; Okamoto, W.; Nishio, K.; Nakagawa, K.

In: Oncogene, Vol. 30, No. 39, 29.09.2011, p. 4097-4106.

Research output: Contribution to journalArticle

Tanizaki, J. ; Okamoto, Isamu ; Fumita, S. ; Okamoto, W. ; Nishio, K. ; Nakagawa, K. / Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification. In: Oncogene. 2011 ; Vol. 30, No. 39. pp. 4097-4106.
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