Suppressor genes in breast cancer: An overview
Over the past 10 years a multitude of oncogenes have been discovered, and considerable progress has been made in the characterization of their biochemical functions/malfunctions [reviewed 1]. Cell-fusion studies have predicted the existence of suppressor genes for both the tumorigenic and metastatic components of cancer progression [2, 3, 4]. The general location of many putative suppressor genes was identified on the basis of chromosomal alterations, usually deletions, often in cancer types with a high risk of inheritance. One characteristic of many suppressor genes postulated to date is their homozygous inactivation in cancer cells, by deletion and/or mutation, consistent with Knudson’s hypothesis . Additional data, including experiments described herein for breast cancer, suggest that structural and/or regulatory alterations to suppressor genes, in the absence of homozygous inactivation, may also impact the cancer phenotype. Transfection experiments, however, remain the only accepted confirmation of a suppressive function. In these experiments the suppressor gene is transfected with a marker gene (usually antibiotic resistance) into tumor cells, and changes to a more ‘normal’ phenotype are noted. These experiments are fraught with difficulties, making their interpretation difficult: Often, transfection of the suppressor gene construct generates significantly fewer antibiotic-resistant colonies than a side-by-side transfection with a control construct. For p53, many of the transfected colonies that grew had p53 mutations . Although there are other possible interpretations, the data suggest that those tumor cells expressing the transfected suppressor gene and exhibiting a more ‘normal’ phenotype do not readily grow out as a colony. This may be due to direct effects on cell division or other changes in differentiation, contact inhibition, senescence, or viability. In no case can it be established that a transfected clone expressing the wild-type suppressor gene, and exhibiting a more ‘normal’ phenotype, did not concurrently require mutation at another chromosomal locus. The difficulty in obtaining stable transfected clonal cell lines expressing the wild-type suppressor gene dictates that transfection experiments be reported in only a few tumor cell types.
KeywordsBreast Cancer Suppressor Gene Human Breast Carcinoma Transfection Experiment Allelic Deletion
Unable to display preview. Download preview PDF.
- 6.Baker, S.J., Markowitz, S., Fearon, E.R., Willson, J.K., Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915.Google Scholar
- 9.Hill, S.M., Rodgers, C.S., Hulten, M.A. (1987) Cytogenetic analysis in human breast carcinoma. II. Seven cases in the triploid/tetraploid range investigated using direct preparations. Cancer Genet. Cytogenet. 24:45–62.Google Scholar
- 10.Genuardi, M., Tishira, H., Anderson, D.E., Saunders, G.F. (1989) Distal deletion of chromosome 1p in ductal carcinoma of the breast. Am. Hum. Genet. 45:73–82.Google Scholar
- 14.Devilee, P., van den Broek, M., Mannens, M., Slater, R., Cornelisse, C.J., Westeerveld, A., Khan, P.M. (1991) Differences in patterns of allelic loss between two common types of adult cancer, breast and colon carcinoma, and Wilm’s tumor of childhood. Int. J. Cancer 47:817–821.PubMedCrossRefGoogle Scholar
- 24.Coles, C., Thompson, A.M., Elder, P.A., Cohen, B.B., MacKenzie, I.M., Cranston, G., Chetty, U., Mackay, J., Macdonald, M., Nakamura, Y., Hoyheim, B., Steel, C.M. (1990) Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis. Lancet 336:761–763.PubMedCrossRefGoogle Scholar
- 26.Chen, L.-C., Neubauer, A., Kurisu, W., Waldman, F.M., Ljung, B.-M., Goodson III, W., Goldman, E.S., Moore II, D., Balazs, M., Liu, E., Mayall, B.H., Smith, H.S. (1991) Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc. Natl. Acad. Sci. U.S.A. 88:3847–3851.PubMedCrossRefGoogle Scholar
- 28.Nigro, J., Baker, S., Presinger, A.C., Jessup, J.M., Hostetter, R., Cleary, K., Bigner, S.H., Davidson, N., Baylin, S., Devilee, P., Glover, T., Collins, F.S., Weston, A., Modali, R., Harris, C.C., Vogelstein, B. (1989) Mutations in the p53 gene occur in diverse human tumor types. Nature 342:705–708.PubMedCrossRefGoogle Scholar
- 30.Varley, J.M., Brammar, W.J., Lane, D.P., Swallow, J.E., Dolan, C., Walker, R.A. (1991) Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Br. J. Cancer 62:408–416.Google Scholar
- 32.Borresen, A.-L., Ottestad, A., Andersen, T.I., Heikkila, R., Jahnsen, T., Tveit, K.M., Nesland, J.M. Amplification and protein over-expression of the neu/Her-2/c-erbB-2 protooncogene in human breast carciomas: Relationship to loss of gene sequences on chromosome 17, family history and prognosis. Genes, chrm. and cancer (in press).Google Scholar
- 38.Devilee, P., van Vliet, M., Kuiers-Dijkshoorn, N., Pearson, P.L., Cornelisse, C.J. (1990) Somatic genetic changes on chromosome 18 in breast carcinomas: Is the DCC gene involved? 311–315.Google Scholar