BCoR-L1 variation and breast cancer

Abstract

Introduction: BRCA1 is involved in numerous essential processes in the cell, and the effects of BRCA1 dysfunction in breast cancer carcinogenesis are well described. Many of the breast cancer susceptibility genes such as BRCA2, p53, ATM, CHEK2, and BRIP1 encode proteins that interact with BRCA1. BCL6 corepressor-like 1 (BCoR-L1) is a newly described BRCA1-interacting protein that displays high homology to several proteins known to be involved in the fundamental processes of DNA damage repair and transcription regulation. BCoR-L1 has been shown to play a role in transcription corepression, and expression of the X-linked BCoR-L1 gene has been reported to be dysregulated in breast cancer subjects. BCoR-L1 is located on the X chromosome and is subject to X inactivation.

Methods: We performed mutation analysis of 38 BRCA1/2 mutation-negative breast cancer families with male breast cancer, prostate cancer, and/or haplotype sharing around BCoR-L1 to determine whether there is a role for BCoR-L1 as a high-risk breast cancer predisposition gene. In addition, we conducted quantitative real-time PCR (qRT-PCR) on lymphoblastoid cell lines (LCLs) from the index cases from these families and a number of cancer cell lines to assess the role of BCoR-L1 dysregulation in cancer and cancer families.

Results: Very little variation was detected in the coding region, and qRT-PCR analysis revealed that BCoR-L1 expression is highly variable in cancer-free subjects, high-risk breast cancer patients, and cancer cell lines. We also report the investigation of a new expression control, DIDO1 (death inducer-obliterator 1), that is superior to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and UBC (ubiquitin C) for analysis of expression in LCLs.

Conclusion: Our results suggest that BCoR-L1 expression does not play a large role in predisposition to familial breast cancer.

Figure 1

BCoR-L1 expression in cancer and normal cell lines. (a) BCoR-L1 expression in cancer and normal cell lines. (b) Mean and standard deviation of BCoR-L1 expression in cancer and normal cell lines. Normal cell lines: ovarian – OSE 64/96, HOSE 17.1; breast – SVCT, Bre80hTERT; prostate – RWPE1. BCoR-L1, BCL6 corepressor-like 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Figure 2

BCoR-L1 haplotype sharing family pedigree detailing carriers of the c.516T>C and c.3608-156C>T variants. = breast cancer-positive; c.516T>C and c.3608-156C>T-positive. = breast cancer-negative; c.516T>C and c.3608-156C>T-positive. □ = breast cancer-negative; c.516T>C and c.3608-156C>T-negative. Circle = female, square = male; subjects marked by small shapes were not available for genotyping. BCoR-L1, BCL6 corepressor-like 1.

Figure 3

BCoR-L1 expression in lymphoblastoid cell lines (LCLs) from breast cancer families. (a) BCoR-L1 expression in LCLs from breast cancer families (normalised to GAPDH). (b) BCoR-L1 expression in LCLs from breast cancer families (normalised to DIDO-1). (c) Mean and standard deviation of BCoR-L1 expression in samples, grouped according to type of family cancer or BCoR-L1 genotype (normalised to GAPDH). (d) Mean and standard deviation of BCoR-L1 expression in samples, grouped according to type of family cancer or BCoR-L1 genotype (normalised to DIDO-1). *Subject also carries a BRCA2 mutation. ^#Subjects from the same BCoR-L1 haplotype sharing family. BCoR-L1, BCL6 corepressor-like 1; DIDO-1, death inducer-obliterator 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Figure 4

Variation in control gene expression. (a) Variation in control gene expression in lymphoblastoid cell lines. (b) Variation in control gene expression in cell lines. DIDO-1, death inducer-obliterator 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; UBC, ubiquitin C.