title: Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The mRNA levels of aromatase and its inducers [tumor necrosis factor alpha (TNF-alpha), 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-alpha 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-alpha, but not IL-6 and COX-2.
authors.affiliation: Department of Surgical Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyoshi
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kenji
authors.initials: K
authors.lastname: Akazawa
authors.forename: Shunji
authors.initials: S
authors.lastname: Kamigaki
authors.forename: Satsuki
authors.initials: S
authors.lastname: Ueda
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Tomoo
authors.initials: T
authors.lastname: Inoue
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Noguchi
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017024:Chemotherapy, Adjuvant; D051546:Cyclooxygenase 2; D000077143:Docetaxel; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008565:Membrane Proteins; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017698:Postmenopause; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015850:Interleukin-6; D008565:Membrane Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D014409:Tumor Necrosis Factor-alpha; D000077143:Docetaxel; D001141:Aromatase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases