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

• Published in: Breast cancer research and treatment Vol. 138; no. 2; pp. 369 - 381
• Main Authors: Wander, Seth A., Zhao, Dekuang, Besser, Alexandra H., Hong, Feng, Wei, Jianqin, Ince, Tan A., Milikowski, Clara, Bishopric, Nanette H., Minn, Andy J., Creighton, Chad J., Slingerland, Joyce M.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2013; Springer; Springer Nature B.V
• Subjects: Animals; B cells; Biological and medical sciences; Bone Neoplasms - mortality; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Cancer research; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cellular biology; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cytoplasm - metabolism; Disease-Free Survival; Female; Gene Expression; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Inhibitor drugs; Kaplan-Meier Estimate; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Motility; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Oncology; Parenting; Phosphoinositide-3 Kinase Inhibitors; Preclinical Study; Pyridones - pharmacology; Pyrimidines - pharmacology; RNA, Small Interfering - genetics; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; Toy industry; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; Cancer invasion; PI3K/mTOR; Motility; Metastasis; p27; Antineoplastic agent; KIP1 Gene; Enzyme; Targeted therapy; Transferases; Malignant tumor; In vitro; Invasion; 1-Phosphatidylinositol 3-kinase; In vivo; Treatment; Mammalian target of rapamycin; Inhibitor; Inhibition; Cancer; Tumor suppressor gene
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-012-2389-6

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.