Down-Regulation of Intratumoral Aromatase Messenger RNA Levels by Docetaxel in Human Breast Cancers

Abstract

Purpose: The reason why chemotherapy induces resistance to subsequent hormonal therapy remains to be clarified in postmenopausal breast cancers. We hypothesized that chemotherapy might down-regulate the intratumoral biosynthesis of estrogens. Thus, we have studied the influence of chemotherapy (docetaxel) on intratumoral aromatase mRNA expression because aromatase is a key enzyme for intratumoral biosynthesis of estrogens. Experimental Design: The mRNA levels of aromatase and its inducers [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)] were determined by a real-time polymerase chain reaction assay in breast cancer tissues obtained before and after neoadjuvant chemotherapy with docetaxel (four cycles of 60 mg/m² every 3 weeks) in 16 postmenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancers. ER and PR levels in tumor tissues were also determined by enzyme immunoassay before and after chemotherapy. Results: The intratumoral aromatase mRNA levels decreased significantly (P < 0.05) after chemotherapy from 0.84 ± 0.28 (mean ± SE) to 0.47 ± 0.28. The intratumoral TNF-α mRNA levels also decreased significantly (P < 0.05) after chemotherapy from 2.40 ± 0.52 to 0.95 ± 0.25. On the contrary, the intratumoral IL-6 and COX-2 mRNA levels showed a marginally significant increase (P = 0.07) and a significant increase (P < 0.05), respectively, after chemotherapy. PR levels showed a marginally significant decrease (P = 0.08) after chemotherapy, whereas ER levels were almost constant before and after chemotherapy. Conclusions: Antitumor activity of docetaxel is mediated, at least in part, through a down-regulation of aromatase expression in tumor tissues, resulting in the suppression of intratumoral estradiol synthesis. Aromatase expression seems to be regulated mostly by TNF-α, but not IL-6 and COX-2.