Identification of tumour suppressor gene(s) involved in breast cancer carcinoma at chromosome region 11q22-q23

Objective

In this research proposal, we seek to identify and clone a tumour suppressor gene located at chromosome region 11q22-q23 which plays an important role in breast cancer development. Partner 1 has previously shown that chromosome 11q13-23 can significantly inhibit tumorigenicity of the breast cancer cell line MCF-7 and has detected loss of heterozygosity (LOH) at region 11q22-q23 in 40% of 62 breast cancer specimens. The minimal overlapping region of LOH was shown to be between the loci D11S35 and D11S29. These results indicated the existence of a tumour suppressor gene in this chromosomal region, whose function was likely related to the inhibition of tumorigenicity observed in MCF-7 cells. In the mean time, with the help of a panel of radiation hybrids, partner 2 completed the genetic map of chromosome 11 with more than 500 precisely located loci. The average distance between loci is about 300-400 Kb, and more than 50 loci are localized between D11S35 and D11S29. The strategy will be as follows: (1) identification of a manageable minimal critical region by (a) correlating tumorigenicity of cell hybrids with the presence of deleted forms of the transferred chromosome 11, and (b) reducing the area of LOH on primary breast tumour DNA specimens; (2) cloning DNA fragments from the minimal critical region in YAC and PAC vectors; (3) construction of a physical map of the region by ordering YACs and PACs in contigs; (4) search for the critical gene will make use of several strategies including the exon trapping and cDNA selection techniques to identify genes residing in the minimal region; (5) cloned genes will be tested for mutations in breast cancer cell lines and primary tumours with LOH in the region of

Programme(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Topic(s)

• 5.3 - Role of gene and gene products in disease aetiology and pathogenesis

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Università degli Studi di Ferrara

Address

Via Luigi Borsari 46
44100 Ferrara
Italy

Participants (3)

Istituto Dermopatico dell'Immacolata

Italy

Address

Via Dei Monti Di Creta 104
00167 Roma

Karolinska Institute

Sweden

Address

6,Blickagangen
14157 Huddinge

The Chancellor, Master and Scholars of the University of Oxford

United Kingdom

Address

Windmill Road
OX3 7BN Oxford, Oxon