Estradiol metabolism: An endocrine biomarker for chemoprevention of human mammary carcinogenesis

Abstract

A relationship between altered metabolism of estradiol (E2) and personal or familial risk for breast cancer suggests that endocrine changes associated with ovarian function may influence initiation or promotion of carcinogenesis. Evidence for a direct effect of E2 on non-involved mammary tissue (target for carcinogenesis) is equivocal. Explant cultures of human mammary terminal duct lobular units (TDLU) from breast cancer patients are utilized to examine whether (i) E2 metabolism in TDLU is altered in response to the chemical carcinogen benzo(a)pyrene [B(a)P], and (ii) perturbed E2 metabolism is modulated by naturally occurring polyunsaturated fatty acids (PUFA) and indole-3-carbinol (I3C). Treatment of TDLU with 40 nM B(a)P resulted in a > 95% decrease in C2/C16α-hydroxylation ratio of E2 relative to that detected in solvent controls. This metabolic alteration was due to a specific increase in E2 C16α-hydroxylation. Exposure of TDLU prior to and during B(a)P treatment with omega-6 PUFA decreased C2/C16α-hydroxylation ratio by 38% (p < 0.001). Treatment with omega-3 PUFA and I3C increased the ratio by 318% and 376% respectively (p < 0.001), due to a specific increase in E2 C2-hydroxylation. Thus, carcinogen-induced perturbation of E2 metabolism in TDLU and its modulation by dietary modulators of rodent mammary tumorigenesis provide evidence for this endocrine biomarker as a clinically relevant endpoint for chemoprevention of mammary carcinogenesis.