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Clin Cancer Res ; 16(7): 2176-86, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20332317

ABSTRACT

PURPOSE: Nuclear receptor coactivator expression and activity may partly explain the complex agonist/antagonist effects of tamoxifen at clinical level. In a preoperative trial, dose reduction from 20 to 1 mg tamoxifen was associated with retained antiproliferative effect on breast cancer. Here, we assessed the gene expression of the steroid receptor coactivators SRC-1, SRC-2/transcription intermediary factor 2, and SRC-3/amplified in breast cancer 1 (AIB1) and the growth factor receptor HER-2/neu under three tamoxifen dose regimens. EXPERIMENTAL DESIGN: Surgical specimens from estrogen receptor-positive breast cancer and adjacent normal breast tissue from 64 patients treated 4 weeks preoperatively with 20, 5, or 1 mg/d tamoxifen and 28 nontreated breast cancer controls were analyzed for coactivator and HER-2/neu mRNA expression using real-time reverse transcription-PCR. The gene expression levels were related to immunohistochemical expression of Ki67, serum levels of insulin-like growth factor I and sex hormone binding globulin, other prognostic factors, and clinical outcome. RESULTS: The coactivators and HER-2/neu mRNA levels were higher in malignant compared with normal tissue (P < 0.001). Tamoxifen significantly increased the expression of coactivators in normal and malignant tissue irrespective of dose, especially for SRC-3/AIB1 (P < 0.001 tamoxifen-treated versus nontreated subjects). SRC-3/AIB1 and HER-2/neu mRNA levels were positively correlated (P = 0.016), but the coactivators could not explain the variability of Ki67, insulin-like growth factor I, and sex hormone binding. Although not significant, SRC-3/AIB1 tended to be higher in subjects with poor clinical outcome and unfavorable prognostic factors. CONCLUSIONS: Increased coactivator mRNA levels seem to be an early response to tamoxifen without dose-response relationship in the 1- to 20-mg range. Clinical and molecular effects of low-dose tamoxifen should be further explored.


Subject(s)
Breast Neoplasms/drug therapy , Breast/drug effects , Carcinoma/drug therapy , Nuclear Receptor Coactivator 3/genetics , Tamoxifen/administration & dosage , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Breast/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinoma/genetics , Carcinoma/metabolism , Dose-Response Relationship, Drug , Double-Blind Method , Drug Resistance, Neoplasm/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic/drug effects , Humans , Middle Aged , Nuclear Receptor Coactivator 3/metabolism , Randomized Controlled Trials as Topic , Tamoxifen/pharmacology
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