Increased 5α-Reductase Type 2 Expression in Human Breast Carcinoma following Aromatase Inhibitor Therapy: The Correlation with Decreased Tumor Cell Proliferation

Tumor cell proliferation and progression of breast cancer are influenced by female sex steroids. However, not all breast cancer patients respond to aromatase inhibitors (AI), and many patients become unresponsive or relapse. Recent studies demonstrate that not only estrogens but also androgens may serve as regulators of estrogen-responsive as well as estrogen-unresponsive human breast cancers. However, the mechanism underlying these androgenic actions has remained relatively unknown. Therefore, in this study, we evaluated the effects of AI upon the expression of enzymes involved in intratumoral androgen production including 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5), 5α-reductase types 1 and 2 (5αRed1 and 5αRed2) as well as androgen receptor (AR) levels and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). Eighty-two postmenopausal invasive ductal carcinoma patients were enrolled in CAAN study from November 2001 to April 2004. Pre- and post-treatment specimens of 29 cases were available for this study. The status of 17βHSD5, 5αRed1, 5αRed2, and Ki67 in pre- and post-treatment specimens were evaluated. The significant increments of 5αRed2 as well as AR were detected in biological response group whose Ki67 LI decreased by more than 40% of the pre-treatment level. This is the first study demonstrating an increment of 5αRed2 and AR in the group of the patients associated with Ki67 decrement following AI treatment. These results suggest that increased 5αRed2 and AR following AI treatment may partly contribute to reduce the tumor cell proliferation through increasing intratumoral androgen concentrations and its receptor.