Role of ERα and Aromatase in Juvenile Gigantomastia

Abstract

Abstract Context Approximately 150 patients with juvenile gigantomastia have been reported in the literature but the underlying biologic mechanisms remain unknown. Objective To conduct extensive clinical, biochemical, immunochemical, and genetic studies in 3 patients with juvenile gigantomastia to determine causative biologic factors. Methods We examined clinical effects of estrogen by blockading estrogen synthesis or its action. Breast tissue aromatase expression and activity were quantitated in 1 patient and 5 controls. Other biochemical markers, including estrogen receptor α (ERα), cyclin D1 and E, p-RB, p-MAPK, p-AKT, BCL-2, EGF-R, IGF-IR β, and p-EGFR were assayed by Western blot. Immunohistochemical analyses for aromatase, ERα and β, PgR, Ki67, sulfotransferase, estrone sulfatase, and 17βHD were performed in all 3 patients. The entire genomes of the mother, father, and patient in the 3 families were sequenced. Results Blockade of estrogen synthesis or action in patients resulted in demonstrable clinical effects. Biochemical studies on fresh frozen tissue revealed no differences between patients and controls, presumably due to tissue dilution from the large proportion of stroma. However, immunohistochemical analysis of ductal breast cells in the 3 patients revealed a high percent of ERα (64.1% ± 7.8% vs reference women 9.6%, range 2.3-15%); aromatase score of 4 (76%-100% of cells positive vs 30.4% ± 5.6%); PgR (69.5% ± 15.2% vs 6.0%, range 2.7%-11.9%) and Ki67 (23.7% ± 0.54% vs 4.2%). Genetic studies were inconclusive although some intriguing variants were identified. Conclusion The data implicate an important biologic role for ERα to increase tissue sensitivity to estrogen and aromatase to enhance local tissue production as biologic factors involved in juvenile gigantomastia.