Pathobiologic characteristics of hereditary breast cancer

Patients with hereditary breast cancer (HBC) present at a young age with breast cancers that show adverse pathological characteristics such as high nuclear grade, negative hormone receptor status, and high proliferation indices. Surprisingly, the clinical course has been reported to be comparable or improved compared with patients with nonhereditary breast cancer (non-HBC). To determine whether there are any molecular markers that might help explain this paradox between pathologically aggressive neoplasms in patients with HBC and the lack of extreme clinically aggressive disease, we studied several molecular parameters in a group of 34 breast cancer patients with mutations in either the BRCA1 or BRCA2 tumor suppressor genes and compared them with a group of 20 breast cancer patients with non-HBC. In general, patients with HBC had tumors that were of higher nuclear grade, contained a higher population of proliferating cells, showed increased expression of DNA topoisomerase II-alpha (topo II-alpha), lacked hormone receptors, and were more likely to show immunopositivity for the p53 tumor suppressor gene. Additionally, tumors from patients with HBC showed a decreased angiogenesis compared with controls. The decreased angiogenesis and the elevated expression of topo II-alpha (an anticancer drug target) may, in part, explain the lack of correlation between clinical course and histological characteristics in patients with HBC.