Molecular Biology of Preliferative Breast Disease

BRCA1 mutations are present in approximately three-fourths of families with ovarian and breast cancer and in about half of families with only breast cancer. The molecule has a zinc-binding ring finger domain suggesting a function in regulation of transcription, but the protein has also been reported to be a secreted product that is able to inhibit tumor cell growth (Ezzell, 1996; Holt et al., 1996; Jensen, R.A. et al., 1996). Athough a single mutation has been found in 1% of the Ashkenase Jewish population, over 100 mutations have been identified, many of which occur in only one or two families (CoUins, 1996). Not all BRCAl mutations are equal.

Mutations in either the amino terminal or carboxy terminal conserved domains result in tumors with higher proliferation rates than mutations at other sites (Sobol et al., 1996). Furthermore, cancer grade segregates by family, some giving rise to more proliferative, aggressive invasive carcinoma than others (Eisinger et al., 1996).

In a study of 202 cases from 36 BRCA1 breast cancer families, only four pure CIS lesions were found, two of which were sporadic cancers, that is, their hosts were not carriers of the mutant alleles (Sun et al., 1996). This finding suggests that, if present in BRCAl patients, DCIS is a very transient stage that rapidly progresses to invasive carcinoma.

BRCAl is seldom mutated in sporadic breast cancer (Xu and Solomon, 1996).

However, allelic imbalance at the BRCAl locus was seen in 74% of DCIS cases (Munn et al., 1996). Thus, the role of BRCAl in sporadic breast cancer is still undetermined.

BRCA2 is a second hereditary breast cancer gene and is involved in site-specific breast cancer families. BRCA2 may account for most of the male breast cancer families but was reported to be mutated in only eight of 49 families with breast cancer only (Phelan et al., 1996). Like BRCAl, the role of BRCA2 in sporadic breast cancer is unclear. Although loss of heterozygosity at the BRCA2 locus is common in sporadic breast cancer, mutations in BRCA2 are rare (Lancaster et al., 1996; Miki et al., 1996).

Fred Raymond Miller
Advances in Oncobiology


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