LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Moore, K.M.; Thomas, G J.; Duffy, S.W.; Warwick, J.; Gabe, R.; Chou, P.; Ellis, I.O.; Green, A.R.; Haider, S.; Brouilette, K.; Saha, A.; Vallath, S.; Bowen, R.; Chelala, C.; Eccles, D.; Tapper, W.J.; Thompson, A.M.; Quinlan, P.; Jordan, L.; Gillett, C.; Brentnall, A.; Violette, S.; Weinreb, P.H.; Kendrew, J.; Barry, S.T.; Hart, I.R.; Jones, J.L.; Marshall, J.F. (2014)
Publisher: Oxford University Press
Languages: English
Types: Article
Subjects: RC0254, Article

Classified by OpenAIRE into

mesheuropmc: skin and connective tissue diseases
BACKGROUND:
Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.

METHODS:
Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.

RESULTS:
High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.

CONCLUSIONS:
Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
    • 2. Slamon DJ, Godolphin W, Jones LA, et  al. Studies of the HER-2/ neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-712.
    • 3. Wong AL, Lee SC. Mechanisms of Resistance to Trastuzumab and Novel Therapeutic Strategies in HER2-Positive Breast Cancer. Int J Breast Cancer. 2012;2012:415170.
    • 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
    • 5. Romond EH, Perez EA, Bryant J, et  al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.
    • 6. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71(5):1515-1519.
    • 7. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11(2):263-275.
    • 8. Lindsley CW, Barnett SF, Layton ME, Bilodeau MT. The PI3K/Akt pathway: recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr Cancer Drug Targets. 2008;8(1):7-18.
    • 9. Ueda Y, Wang S, Dumont N, et  al. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor betainduced cell motility. J Biol Chem. 2004;279(24):505-513.
    • 10. Wang SE, Shin I, Wu FY, Friedman DB, Arteaga CL. HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor beta. Cancer Res. 2006;66(19):9591-9600.
    • 11. Muraoka RS, Koh Y, Roebuck LR, et  al. Increased malignancy of Neuinduced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol. 2003;23(23):8691-8703.
    • 12. Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 1990;110(4):1361-1367.
    • 13. Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319-328.
    • 14. Hazelbag S, Kenter GG, Gorter A, et al. Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J Pathol. 2007;212(3):316-324.
    • 15. Bates RC, Bellovin DI, Brown C, et  al. Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 2005;115(2):339-347.
    • 16. Elayadi AN, Samli KN, Prudkin L, et al. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Res. 2007;67(12):5889-5895.
    • 17. Breuss JM, Gallo J, DeLisser HM, et al. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 1995;108 (Pt 6):2241-2251.
    • 18. Van Aarsen LA, Leone DR, Ho S, et  al. Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism. Cancer Res. 2008;68(2):561-570.
    • 19. Allen MD, Clark SE, Dawoud MM, et  al. Altered Microenvironment Promotes Progression of Pre-Invasive Breast Cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Clin Cancer Res. 2014;20(2):344-357.
    • 20. Barczyk M, Carracedo, S. & Gullberg, D. Integrins. Cell Tissue Research. 2012;339(1):269-280.
    • 21. Hu M, Yao J, Carroll DK, et  al. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell. 2008;13(5):394-406.
    • 22. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer. 2005;41(12):1690-1696.
    • 23. Rakha EA, El-Rehim DA, Paish C, et al. Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer. 2006;42(18):3149-3156.
    • 24. Abd El-Rehim DM, Pinder SE, Paish CE, et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol. 2004;203(2):661-671.
    • 25. Crowder MJ HD. Monographs on Statistics and Applied Probability. 1, Editors, Cox DR, Isham V, Keiding N, Reid N & Tong H. London: Chapman & Hall; 1990.
    • 26. Curtis C, Shah SP, Chin SF, et al.The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346-352.
    • 27. Lewis GD, Lofgren JA, McMurtrey AE, et al. Growth regulation of human breast and ovarian tumor cells by heregulin: Evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res. 1996;56(6):1457-1465.
    • 28. Cheang MC, Chia, SK, Voduc, D, et  al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736-750.
    • 29. Slamon DJ, Leyland-Jones B, Shak S, et  al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.
    • 30. Muraoka-Cook RS, Shin I, Yi JY, et al. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene. 2006;25(24):3408-3423.
    • 31. Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61(Suppl 2):1-13.
    • 32. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002;1(9):707-717.
    • 33. Eberlein C, Kendrew J, McDaid K, et  al. A human monoclonal antibody 264RAD targeting alphavbeta6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene. 2013;32(37):4406-4416.
    • 34. Violette S, Sheppard D, Rosas IO, et al. Identification Of Biomarkers To Monitor The Activity Of STX-100, A Humanized Anti-αvβ6 Antibody, In A Phase 2a Trial In Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2012;185:A2659.
  • No related research data.
  • No similar publications.

Share - Bookmark

Funded by projects

  • RCUK | Establishing the utility a...

Cite this article