The etiology of human breast cancer is thought to involve a complex interplay of genetic, hormonal, and dietary factors that are superimposed on the physiological status of the host. Attempts to derive a cohesive picture of how these factors participate in the etiology of breast cancer have been compounded by a lack of information on specific mutations associated with the initiation and progression of the disease. We have undertaken an ongoing program aimed at determining, on a molecular level, those genetic alterations in primary breast tumor DNA that have a statistically significant association with the patients history, characteristics of the tumor and the patients prognosis. In previous studies, we have detected frequent amplification of the c-myc, int-2, and c-erbB2 proto-oncogenes and the frequent loss of heterozygosity (LOH) on chromosomes lq, 3p, llp and 13q. Our current results demonstrate that LOH also frequently occurs on chromosomes lp, 17p, 17q, and 18q. LOH on chromosome 17q has a significant association (p< 0.02) with estrogen receptor negative tumors and LOH is associated (p<0.04) with histopathological grade III tumors. We have also found associations between specific mutations. ]For instance, one subset of tumors could be defined by the frequent presence of LOH on chromosomes 11p, 17p, and 18q. Another subset of tumors contained LOH on chromosomes 1p, 13q, and 17q. These results suggest that different subsets of mutations, possibly acting in a complimentary way, are a consequence of the heterogeneous nature of the etiologic factors that provide the selective pressure for the clonal outgrowth of cells containing particular mutations during breast carcinogenesis. We have begun to identify the target genes affected by LOH. For example, on chromosome 17p, a likely candidate is the p53 gene. We have found that the remaining allele of p53, in tumors having LOH on 17p, may also contain a point mutation. On chromosome 17q, we have found LOH at the nm23 gene. This gene is tightly linked to the hereditary breast cancer locus.
