PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: Implications for targeted therapy

Seth A. Wander, Dekuang Zhao, Alexandra H. Besser, Feng Hong, Jianqin Wei, Tan Ince, Clara Milikowski, Nanette Bishopric, Andy J. Minn, Chad J. Creighton, Joyce M Slingerland

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Oncogenic PI3K/mTOR activation is frequently observed in human cancers and activates cell motility via p27 phosphorylations at T157 and T198. Here we explored the potential for a novel PI3K/mTOR inhibitor to inhibit tumor invasion and metastasis. An MDA-MB-231 breast cancer line variant, MDA-MB-231-1833, with high metastatic bone tropism, was treated with a novel catalytic PI3K/mTOR inhibitor, PF-04691502, at nM doses that did not impair proliferation. Effects on tumor cell motility, invasion, p27 phosphorylation, localization, and bone metastatic outgrowth were assayed. MDA-MB-231-1833 showed increased PI3K/mTOR activation, high levels of cytoplasmic p27pT157pT198 and increased cell motility and invasion in vitro versus parental. PF-04691502 treatment, at a dose that did not affect proliferation, reduced total and cytoplasmic p27, decreased p27pT157pT198 and restored cell motility and invasion to levels seen in MDA-MB-231. p27 knockdown in MDA-MB-231-1833 phenocopied PI3K/mTOR inhibition, whilst overexpression of the phosphomimetic mutant p27T157DT198D caused resistance to the anti-invasive effects of PF-04691502. Pre-treatment of MDA-MB-231-1833 with PF-04691502 significantly impaired metastatic tumor formation in vivo, despite lack of antiproliferative effects in culture and little effect on primary orthotopic tumor growth. A further link between cytoplasmic p27 and metastasis was provided by a study of primary human breast cancers which showed cytoplasmic p27 is associated with increased lymph nodal metastasis and reduced survival. Novel PI3K/mTOR inhibitors may oppose tumor metastasis independent of their growth inhibitory effects, providing a rationale for clinical investigation of PI3K/mTOR inhibitors in settings to prevent micrometastasis. In primary human breast cancers, cytoplasmic p27 is associated with worse outcomes and increased nodal metastasis, and may prove useful as a marker of both PI3K/mTOR activation and PI3K/mTOR inhibitor efficacy.

Original languageEnglish
Pages (from-to)369-381
Number of pages13
JournalBreast Cancer Research and Treatment
Volume138
Issue number2
DOIs
StatePublished - Apr 1 2013

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Phosphatidylinositol 3-Kinases
Neoplasm Metastasis
Neoplasms
Cell Movement
Therapeutics
Breast Neoplasms
Phosphorylation
In Vitro Techniques
Bone and Bones
Neoplasm Micrometastasis
Tropism
Lymph
Growth
Survival
2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one

Keywords

  • Cancer invasion
  • Metastasis
  • Motility
  • p27
  • PI3K/mTOR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro : Implications for targeted therapy. / Wander, Seth A.; Zhao, Dekuang; Besser, Alexandra H.; Hong, Feng; Wei, Jianqin; Ince, Tan; Milikowski, Clara; Bishopric, Nanette; Minn, Andy J.; Creighton, Chad J.; Slingerland, Joyce M.

In: Breast Cancer Research and Treatment, Vol. 138, No. 2, 01.04.2013, p. 369-381.

Research output: Contribution to journalArticle

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