Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Targeting the Akt/mTOR pathway in Brca1-deficient cancers

Oncogene volume 30, pages 2443–2450 (2011)Cite this article

Subjects

Abstract

The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1-deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Aaltonen K, Amini RM, Landberg G, Eerola H, Aittomaki K, Heikkila P et al. (2009). Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer. Breast Cancer Res Treat 113: 75–82.

    Article  CAS  Google Scholar 

  • Aleskandarany MA, Rakha EA, Ahmed MA, Powe DG, Ellis IO, Green AR . (2010). Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat (e-pub ahead of print 9 July 2010).

  • Bellacosa A, Kumar CC, Di CA, Testa JR . (2005). Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94: 29–86.

    Article  CAS  Google Scholar 

  • Brodie SG, Deng CX . (2001). BRCA1-associated tumorigenesis: what have we learned from knockout mice? Trends Genet 17: S18–S22.

    Article  CAS  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.

    Article  CAS  Google Scholar 

  • Chen ML, Xu PZ, Peng XD, Chen WS, Guzman G, Yang X et al. (2006). The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev 20: 1569–1574.

    Article  CAS  Google Scholar 

  • Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T et al. (2001). Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 15: 2203–2208.

    Article  CAS  Google Scholar 

  • Deng CX . (2006). BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 34: 1416–1426.

    Article  CAS  Google Scholar 

  • Diaz R, Nguewa PA, az-Gonzalez JA, Hamel E, Gonzalez-Moreno O, Catena R et al. (2009). The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer 100: 932–940.

    Article  CAS  Google Scholar 

  • Dinesh KP, Devaraj H, Murugan V, Rajaraman R, Niranjali S . (2006). Analysis of loss of heterozygosity and immunohistochemistry in BRCA1 gene in sporadic breast cancers. Mol Cell Biochem 287: 177–183.

    Article  CAS  Google Scholar 

  • Ding SL, Sheu LF, Yu JC, Yang TL, Chen B, Leu FJ et al. (2004). Expression of estrogen receptor-alpha and Ki67 in relation to pathological and molecular features in early-onset infiltrating ductal carcinoma. J Biomed Sci 11: 911–919.

    CAS  PubMed  Google Scholar 

  • Efeyan A, Sabatini DM . (2010). mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 22: 169–176.

    Article  CAS  Google Scholar 

  • Faivre S, Kroemer G, Raymond E . (2006). Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5: 671–688.

    Article  CAS  Google Scholar 

  • Guertin DA, Sabatini DM . (2007). Defining the role of mTOR in cancer. Cancer Cell 12: 9–22.

    Article  CAS  Google Scholar 

  • Guertin DA, Sabatini DM . (2009). The pharmacology of mTOR inhibition. Sci Signal 2: e24.

    Article  Google Scholar 

  • Hay N . (2005). The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8: 179–183.

    Article  CAS  Google Scholar 

  • Inoki K, Corradetti MN, Guan KL . (2005). Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19–24.

    Article  CAS  Google Scholar 

  • Inoki K, Guan KL . (2006). Complexity of the TOR signaling network. Trends Cell Biol 16: 206–212.

    Article  CAS  Google Scholar 

  • Inoki K, Li Y, Zhu T, Wu J, Guan KL . (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4: 648–657.

    Article  CAS  Google Scholar 

  • Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A et al. (2005). AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207: 139–146.

    Article  CAS  Google Scholar 

  • Lee CH, Inoki K, Guan KL . (2007). mTOR pathway as a target in tissue hypertrophy. Annu Rev Pharmacol Toxicol 47: 443–467.

    Article  CAS  Google Scholar 

  • Ludwig T, Fisher P, Ganesan S, Efstratiadis A . (2001). Tumorigenesis in mice carrying a truncating Brca1 mutation. Genes Dev 15: 1188–1193.

    Article  CAS  Google Scholar 

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.

    Article  CAS  Google Scholar 

  • Narod SA, Foulkes WD . (2004). BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4: 665–676.

    Article  CAS  Google Scholar 

  • O'Reilly T, McSheehy PM . (2010). Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol 3: 65–79.

    Article  Google Scholar 

  • Pallares J, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J et al. (2005). Survivin expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3. Int J Gynecol Pathol 24: 247–253.

    Article  Google Scholar 

  • Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L et al. (2005). Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7: 193–204.

    Article  CAS  Google Scholar 

  • Sabatini DM . (2006). mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6: 729–734.

    Article  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM, O'Reilly KE, Rojo F et al. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Science 307: 1098–1101.

    Article  CAS  Google Scholar 

  • Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL et al. (2001). AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 159: 431–437.

    Article  CAS  Google Scholar 

  • Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT . (1995). Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9: 444–450.

    Article  CAS  Google Scholar 

  • Tran H, Brunet A, Griffith EC, Greenberg ME . (2003). The many forks in FOXO's road. Sci STKE 2003: RE5.

    PubMed  Google Scholar 

  • van der GP, van Diest PJ, Menko FH, Bart J, de Vries EG, van der WE . (2009). Molecular profile of ductal carcinoma in situ of the breast in BRCA1 and BRCA2 germline mutation carriers. J Clin Pathol 62: 926–930.

    Article  Google Scholar 

  • Wickenden JA, Watson CJ . (2010). Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Res 12: 202.

    Article  Google Scholar 

  • Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K et al. (1999). Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 21: 236–240.

    Article  CAS  Google Scholar 

  • Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN et al. (2008). Negative regulation of AKT activation by BRCA1. Cancer Res 68: 10040–10044.

    Article  CAS  Google Scholar 

  • Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA et al. (2001). Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28: 266–271.

    Article  CAS  Google Scholar 

  • Xue Q, Hopkins B, Perruzzi C, Udayakumar D, Sherris D, Benjamin LE . (2008). Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res 68: 9551–9557.

    Article  CAS  Google Scholar 

  • Yang Q, Wesch H, Mueller KM, Bartsch H, Wegener K, Hollstein M . (2000). Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation. Br J Cancer 82: 763–766.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Junjie Chen for providing the wild type and mutant GST-Brca1-BRCT constructs and Bing-Hua Jiang for providing Akt1-473D construct and Thomas Ludwig for providing Brca1+/+ and Brca1tr/tr MEFs. We thank Buck Rogers, Andrei Laszlo and Xiaowei Wang for proof-reading. This work is supported in part by grants from the Susan G Komen Foundation (QY), Siteman Cancer Center Award (QY) and NIH CA129440 (QY).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA

    T Xiang, Y Jia & Q Yang

  2. Paloma Pharmaceuticals, Jamaica Plain, MA, USA

    D Sherris

  3. Department of Medicine and Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA

    S Li

  4. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, St Louis, MO, USA

    H Wang

  5. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    D Lu

Authors
  1. T Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Sherris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Q Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Q Yang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiang, T., Jia, Y., Sherris, D. et al. Targeting the Akt/mTOR pathway in Brca1-deficient cancers. Oncogene 30, 2443–2450 (2011). https://doi.org/10.1038/onc.2010.603

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.603

Keywords

This article is cited by

Search

Advanced search

Quick links