Since both estradiol treatment and ras-oncogene overexpression enhance tumorigenicity of hormone-dependent breast-cancer cells, we studied the effects of estrogen and of the activated v-Ha-ras oncogene on NK susceptibility of MCF-7 human breast-cancer cells.
Lod scores for close linkage of each candidate sequence to breast cancer were -19.6 for HRAS, -12.3 for KRAS2, -1.0 for NRAS, -6.0 for MYC, -6.1 for MYB, -8.2 for ERBA2, -7.9 for INT2, and -5.1 for RAF1.
The findings on Ha-ras and other informative loci are consistent with the possibility that a tumour suppressor gene involved in the early stages of breast cancer is located on the short arm of chromosome 11.
Enhanced Ha-ras expression was documented in 66% of breast and 100% of colon carcinomas as compared with their normal counterparts, with levels in breast carcinomas ranging from 10.1 to 50.4 pg ras p21/micrograms protein and those in colon carcinomas ranging from 18.4 to 51.7 pg ras p21/micrograms protein.
The study was done on a total of 51 lung, colon and breast carcinoma tumors using a panel of oligonucleotides coding for the wild type and all possible mutations in codons 12 and 61 of c-K-ras gene.
The frequency of rare c-Ha-ras-1 alleles and hence genotypes composed of two rare alleles was increased in the breast cancer population (P less than .001).
Correlation with clinicopathological data showed, however, that the loss of one H-ras-1 allele in breast carcinoma DNAs is significantly linked to histological Grade III tumors, the lack of estrogen and/or progesterone receptors, and the subsequent occurrence of distal metastasis.
Genetic alterations have been described in breast carcinomas under the headings of loss of heterozygosity (1p, 3p, 7q, 11p, 17p, 17 and 18q), mutations (p53, c-H-ras-1), and/or gene amplifications (c-myc, int-2/FGF3, and c-erbB-2/neu).
Approximately one fifth of the breast cancer patients in this analysis (disease-free and recurrent) expressed only a single oncogene marker (c-fos, c-myc, Ha-ras, or p53); one quarter of patients with recurrent disease expressed only one oncogene protein.
The results obtained with atypical hyperplasia, a doubtful proliferating lesion, suggests that p21 c-Ha-ras protein expression is not restricted to breast carcinomas.
Several epidemiologic studies suggest that individuals carrying rare alleles at a minisatellite flanking the HRAS locus are at increased risk of cancer, including breast cancer.
There may be more common mutations in other genes (such as ATM, HRAS1) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases.
We analyzed 66 independent cases from sib pairs affected with breast cancer that had previously been collected during an investigation of pathogenetic-allele-sharing at the HRAS1 mini-satellite locus.