TY - JOUR

T1 - ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma

AU - Porter, Sarah

AU - Span, Paul N

AU - Sweep, Fred C G J

AU - Tjan-Heijnen, Vivianne C G

AU - Pennington, Caroline J

AU - Pedersen, Tanja Xenia

AU - Johnsen, Morten

AU - Lund, Leif R

AU - Rømer, John

AU - Edwards, Dylan R

N1 - Keywords: ADAM Proteins; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Prognosis; Survival Rate

PY - 2006

Y1 - 2006

N2 - We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by real-time PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall survival (OS) (hazard ratio (HR) = 2.20, 95% C.I. = 1.29-3.74, p = 0.004) and confirmed ADAMTS15 as a predictor of prolonged relapse-free survival (RFS) (HR = 0.54, 95% C.I. = 0.32-0.89, p = 0.016). We explored the differences in survival of the 4 groups that could be categorized based on the expression levels of ADAMTS8 and ADAMTS15. For both RFS and OS, the group with high ADAMTS8 and low ADAMTS15 expression had a particularly poor prognosis. This group had a 3-fold higher chance of recurrence (HR = 3.03, 95% C.I. = 1.49-6.15, p = 0.001) and a greater than 5-fold higher chance of death (HR = 5.40, 95% C.I. = 2.16-13.5, p < 0.001) than the most favorable prognostic group. This prediction of poor prognosis by ADAMTS8 and ADAMTS15 expression was found to be independent of other classical clinicopathological factors. Results observed in FVB-PyMT mice, a robust transgenic model of highly metastatic breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma.

AB - We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by real-time PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall survival (OS) (hazard ratio (HR) = 2.20, 95% C.I. = 1.29-3.74, p = 0.004) and confirmed ADAMTS15 as a predictor of prolonged relapse-free survival (RFS) (HR = 0.54, 95% C.I. = 0.32-0.89, p = 0.016). We explored the differences in survival of the 4 groups that could be categorized based on the expression levels of ADAMTS8 and ADAMTS15. For both RFS and OS, the group with high ADAMTS8 and low ADAMTS15 expression had a particularly poor prognosis. This group had a 3-fold higher chance of recurrence (HR = 3.03, 95% C.I. = 1.49-6.15, p = 0.001) and a greater than 5-fold higher chance of death (HR = 5.40, 95% C.I. = 2.16-13.5, p < 0.001) than the most favorable prognostic group. This prediction of poor prognosis by ADAMTS8 and ADAMTS15 expression was found to be independent of other classical clinicopathological factors. Results observed in FVB-PyMT mice, a robust transgenic model of highly metastatic breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma.

U2 - 10.1002/ijc.21476

DO - 10.1002/ijc.21476

M3 - Journal article

C2 - 16152618

VL - 118

SP - 1241

EP - 1247

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 5

ER -