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.
KeywordsZinc Agar Estrogen Half Life Osteosarcoma
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