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Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes

Authors' Affiliations: ¹ The Breakthrough Toby Robins Breast Cancer Research Centre at The Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories; ² Department of Oncology, King's College London School of Medicine, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom; ³ School of Information Systems, Computing and Maths, Brunel University, Uxbridge, Middlesex, United Kingdom; ⁴ Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom; and ⁵ Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy

Requests for reprints: Tim Crook, The Breakthrough Toby Robins Breast Cancer Research Centre at The Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 20-7153-5504; Fax: 20-7153-5340; E-mail: tim.crook{at}icr.ac.uk.

Purpose: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer.

Experimental Design: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas.

Results: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P = 0.008) and disease-free survival (DFS) following surgery (P = 0.04) and worse DFS following adjuvant chemotherapy (P = 0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P = 0.10) and decreased DFS (P = 0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P = 0.001) and DFS (P < 0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P < 0.001).

Conclusions: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.