Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1057–1066 | Cite as

Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer

  • Haiyan Li
  • Jun Lin
  • Xiaokai Wang
  • Guangyu Yao
  • Liping Wang
  • Hang Zheng
  • Cuilan Yang
  • Chunhong Jia
  • Anling Liu
  • Xiaochun Bai
Preclinical Study

Abstract

Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.

Keywords

Mammalian target of rapamycin complex 2 Breast cancer Apoptosis Migration Rapamycin mTOR kinase inhibitor 

Supplementary material

10549_2012_2036_MOESM1_ESM.doc (5.3 mb)
Supplementary material 1 (DOC 5456 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Haiyan Li
    • 1
  • Jun Lin
    • 1
  • Xiaokai Wang
    • 2
  • Guangyu Yao
    • 3
  • Liping Wang
    • 4
  • Hang Zheng
    • 5
  • Cuilan Yang
    • 1
  • Chunhong Jia
    • 1
  • Anling Liu
    • 1
  • Xiaochun Bai
    • 1
  1. 1.Department of Cell BiologySouthern Medical UniversityGuangzhouChina
  2. 2.Department of OrthopedicThe Third Affiliated Hospital of Southern Medical UniversityGuangzhouChina
  3. 3.Breast Center, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  4. 4.Department of Obstetrics and Gynecology, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  5. 5.The Oncology Center of Nanfang HospitalSouthern Medical UniversityGuangzhouChina

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