Role of ERα and aromatase in juvenile gigantomastia.

CONTEXT: Approximately 150 patients with juvenile gigantomastia have been reported in the literature but the underlying biologic mechanisms remain unknown.

OBJECTIVE: Conduct extensive clinical, biochemical, immunochemical, and genetic studies in three patients with juvenile gigantomastia to determine causative biologic factors.

DESIGN: We examined clinical effects of estrogen by blockading estrogen synthesis or its action. Breast tissue aromatase expression and activity were quantitated in one patient and five controls. Other biochemical markers including ERα, Cyclin D1 and E, p-RB, p-MAPK, p-AKT, BCL-2, EGF-R, IGF-IR β, and p-EGFR. Immunohistochemical analyses for aromatase, ERα and β, PGR, Ki67, sulfotransferase, estrone sulfatase, and 17βHD were performed in all three patients. The entire genome of the mother, father, and patient in the three families was 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, Immunohistochemically analysis of ductal breast cells in the three patients revealed a high percent of ERα (i.e. 64.1 ± 7.8% vs normal women 9.6% -range 2.3-15%); aromatase score of 4 (76-100% of cells positive) versus 30.4 ± 5.6%); PgR (69.5 ± 15.2% versus 6.0% -range 2.7-11.9%) and Ki67 (23.7 ± 0.54% versus 4.2%). Genetic studies were inconclusive though 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.