Functional evidence for a breast cancer growth suppressor gene on chromosome 17

Abstract

Rearrangements or deletions of chromosome 17 are the most frequently observed genetic changes identified in breast tumors. Molecular analyses suggest that in addition to the p53 gene on 17p13.1 there may be at least three other tumor suppressor genes on chromosome 17 involved in breast cancer. Regions of loss of heterozygosity (LOH) identified on 17p13.3 and 17q12-qter occur frequently in breast tumors, and the BRCA-1 gene has been mapped to 17q21 by genetic linkage analysis. Here we provide biological evidence for the presence of a growth suppressor gene(s) on chromosome 17 that results in the in vitro growth suppression of the p53 wild-type MCF 7 breast cancer cell line. We have introduced a normal chromosome 17 into MCF 7 cells by microcell-mediated chromosome transfer (MMCT), and demonstrate that cells growth arrest before 10 to 12 population doublings. In contrast, the introduction of a normal chromosome 13 had no effect upon growth of these cells either in vitro or in vivo. These data provide direct functional evidence for the presence of a growth suppressor gene(s) on chromosome 17, which is not p53, and which may represent one of several gene(s) that play a critical role in the development of breast cancer.

Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

“…Analysis of the immortal phenotype has revealed several genetic alterations that are important to the process including the dysfunction of p53, INK4A and a gene on chromosome 3p that represses telomerase activity (Loughran et al, 1997;Parkinson et al, 1997). In addition, microcell-mediated monochromosome transfer (MMCT) experiments suggest that other cancer mortality genes may exist (Casey et al, 1993;Hensler et al, 1994;Karlsson et al, 1996;Koi et al, 1993;Ning et al, 1991;Ogata et al, 1993;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;Wang et al, 1992). Furthermore, loss of heterozygosity (LOH) at some of these other chromosomal loci, including the long arm of chromosome 4, supports a role for the dysfunction of these putative mortality genes in the immortality of human SCCs (Loughran et al, 1997).…”

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

“…Furthermore, LOH at YNZ22 can occur in the absence of p53 mutation, deletion or over-expression (Cornelis et al, 1994;Thompson et al, 1998) suggesting both regions may be of clinical importance in sporadic breast cancer Liscia et al, 1999). In addition, supportive evidence for the involvement of a tumour suppressor gene, distinct from p53 on chromosome 17p, is strengthened by the functional suppression of malignancy observed following the transfection of chromosome 17 (but not with chromosome 13) into breast cancer cell lines by micro cellmediated chromosome transfer and analysis of the resulting deletions (Casey et al, 1993;Theile et al, 1995). LOH at 17p13.3 is also associated with an aggressive phenotype being significantly correlated with disease recurrence and death due to breast cancer Nagai et al, 1995).…”

Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

“…Genetic analysis of the immortal phenotype has revealed several genetic alterations that are important to the process including the dysfunction of p53, INK4A and a gene on chromosome 3p that represses telomerase activity (Loughran et al, 1997;Parkinson et al, 1997). In addition, microcell-mediated monochromosome transfer (MMCT) experiments suggest that other cancer mortality genes may exist (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001;Forsyth et al, 2002). Loss of heterozygosity (LOH) at some of these chromosomal loci supports a role for the dysfunction of these putative mortality genes in the immortality of human SCCs (Loughran et al, 1997;Forsyth et al, 2002).…”

“…Previous investigations have used the technique of monochromosome transfer to induce proliferation arrest in human and rodent cancer lines (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Banga et al, 1997;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001) and have attempted to identify the genes responsible by the extensive deletion analysis of segregant colonies that continue to proliferate (see for example, Rimessi et al, 1994;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Forsyth et al, 2002). These studies have shown that, in some instances, the commonly deleted regions contain known antiproliferative genes (England et al, 1996;Robertson et al, 1998) or tumour suppressor genes (Cheng et al, 1998;Lo et al, 2001).…”