Oncotarget

Research Papers:

CD44 increases the efficiency of distant metastasis of breast cancer

Suzanne McFarlane _, Jonathan A. Coulter, Paul Tibbits, Anthony O’Grady, Cheryl McFarlane, Nicola Montgomery, Ashleigh Hill, Helen O. McCarthy, Leonie S. Young, Elaine W. Kay, Clare M. Isacke and David J.J. Waugh

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Oncotarget. 2015; 6:11465-11476. https://doi.org/10.18632/oncotarget.3410

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Abstract

Suzanne McFarlane1, Jonathan A. Coulter1, Paul Tibbits2, Anthony O'Grady2, Cheryl McFarlane1, Nicola Montgomery1, Ashleigh Hill1, Helen O. McCarthy4, Leonie S. Young2, Elaine W. Kay2, Clare M. Isacke3, David J.J. Waugh1

1Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland

2Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland

3Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

4School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland

Correspondence to:

David J.J. Waugh, e-mail: [email protected]

Keywords: CD44, metastasis, breast cancer

Received: August 21, 2014     Accepted: February 19, 2015     Published: March 19, 2015

ABSTRACT

Metastasis is the predominant cause of death from cancer yet we have few biomarkers to predict patients at increased risk of metastasis and are unable to effectively treat disseminated disease. Analysis of 448 primary breast tumors determined that expression of the hylauronan receptor CD44 associated with high grade (p = 0.046), ER- (p = 0.001) and PR-negative tumors (p = 0.029), and correlated with increased distant recurrence and reduced disease-free survival in patients with lymph-node positive or large tumors. To determine its functional role in distant metastasis, CD44 was knocked-down in MDA-MB-231 cells using two independent shRNA sequences. Loss of CD44 attenuated tumor cell adhesion to endothelial cells and reduced cell invasion but did not affect proliferation in vitro. To verify the importance of CD44 to post-intravasation events, tumor formation was assessed by quantitative in vivo imaging and post-mortem tissue analysis following an intra-cardiac injection of transfected cells. CD44 knock-down increased survival and decreased overall tumor burden at multiple sites, including the skeleton in vivo. We conclude that elevated CD44 expression on tumour cells within the systemic circulation increases the efficiency of post-intravasation events and distant metastasis in vivo, consistent with its association with increased distant recurrence and reduced disease-free survival in patients.


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