title: CD44 increases the efficiency of distant metastasis of breast cancer.
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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McFarlane
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coulter
authors.affiliation: Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Tibbits
authors.affiliation: Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Anthony
authors.initials: A
authors.lastname: O'Grady
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Cheryl
authors.initials: C
authors.lastname: McFarlane
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Montgomery
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Hill
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Helen O
authors.initials: HO
authors.lastname: McCarthy
authors.affiliation: Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
authors.affiliation: Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Kay
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: David J J
authors.initials: DJ
authors.lastname: Waugh
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D018572:Disease-Free Survival; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D010641:Phenotype; D016016:Proportional Hazards Models; D034622:RNA Interference; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors
keywords: CD44; breast cancer; metastasis