Background: The biotransformation of the natural estrogen 17beta-estradiol (E2) via the C16alpha-hydroxylation pathway is elevated in patients with breast cancer, in subjects at increased risk for developing breast cancer, and in c-Ha-ras-initiated mouse mammary epithelial cells. Purpose: To determine whether differences in the extent of E2 C16alpha-hydroxylation are related to the risk of developing breast cancer, we examined the extent of biotransformation of E2 via the C16alpha-hydroxylation pathway in the mammary terminal duct lobular units (TDLUs), epithelial organoids that are a presumptive target site of human breast carcinogenesis, and in nontarget component mammary fat tissue. Methods: Noninvolved mammary tissue was obtained from four patients undergoing reduction mammoplasty and from four undergoing mastectomy for breast cancer. A radiometric assay that measures (H2O)-H-3 formation caused by stoichiometric H-3 exchange from [C16alpha-H-3]E2 was utilized to compare the relative extent of C16alpha-hydroxylation in explant cultures of TDLUs and mammary fat. Results: The extent of E2 C16alpha-hydroxylation was 1.83-fold higher (95% confidence interval [CI] = 1.71-1.97) in the TDLUs from reduction mammoplasty (i.e., ''low-risk'') patients and 7.96-fold higher (95% CI = 6.38-10.55) in the TDLUs from mastectomy (i.e., ''high-risk'') patients than in the corresponding values observed in the mammary fat. In the TDLUs obtained from the patients undergoing mastectomy for cancer, the extent of this metabolism was 4.56-fold higher (95% CI = 3.97-5.33) than that observed in TDLUs obtained from reduction mammoplasty patients who did not have cancer. Conclusion: The increase in the extent of C16alpha-hydroxylation of E2 in the epithelial organoids of the human breast, TDLUs in particular, may be an important factor for breast cancer induction. This upregulation may represent an endocrine biomarker for the risk of developing breast cancer. Implication: A larger prospective study is required to confirm the clinical significance of this endocrine biomarker.
