A novel role of sodium butyrate in the regulation of cancer-associated aromatase promoters I.3 and II by disrupting a transcriptional complex in breast adipose fibroblasts

被引:42
作者
Deb, S [1 ]
Zhou, JF [1 ]
Amin, SA [1 ]
Gonca, IA [1 ]
Bertan, YM [1 ]
Zihong, L [1 ]
Bulun, SE [1 ]
机构
[1] Northwestern Univ, Div Reprod Biol Res, Feinberg Sch Med, Chicago, IL 60611 USA
关键词
D O I
10.1074/jbc.M508498200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The aromatase gene encodes the key enzyme for estrogen formation. Aromatase enzyme inhibitors eliminate total body estrogen production and are highly effective therapeutics for postmenopausal breast cancer. A distal promoter (I.4) regulates low levels of aromatase expression in tumor-free breast adipose tissue. Two proximal promoters (I.3/II) strikingly induce in vivo aromatase expression in breast fibroblasts surrounding malignant cells. Treatment of breast fibroblasts with medium conditioned with malignant breast epithelial cells (MCM) or a surrogate hormonal mixture (dibutyryl (Bt(2)) cAMP plus phorbol diacetate (PDA)) induces promoters I.3/II. The mechanism of promoter-selective expression, however, is not clear. Here we reported that sodium butyrate profoundly decreased MCM- or Bt(2)cAMP + PDA-induced promoter I.3/II-specific aromatase mRNA. MCM, Bt(2)cAMP + PDA, or sodium butyrate regulated aromatase mRNA or activity only via promoters I.3/II but not promoters I.1 or I.4 in breast, ovarian, placental, and hepatic cells. Mechanistically, recruitment of phosphorylated ATF-2 by a CRE (-211/-199, promoter I.3/II) conferred inductions by MCM or Bt(2)cAMP + PDA. Chromatin immunoprecipitation-PCR and immunoprecipitation-immunoblotting assays indicated that MCM or Bt(2)cAMP + PDA stabilized a complex composed of phosphorylated ATF-2, C/EBP beta, and cAMP-response element-binding protein (CREB)-binding protein in the common regulatory region of promoters I.3/II. Overall, histone acetylation patterns of promoters I.3/II did not correlate with sodium butyrate-dependent silencing of promoters I.3/II. Sodium butyrate, however, consistently disrupted the activating complex composed of phosphorylated ATF-2, C/EBP beta, and CREB-binding protein. This was mediated, in part, by decreased ATF-2 phosphorylation. Together, these findings represent a novel mechanism of sodium butyrate action and provide evidence that aromatase activity can be ablated in a signaling pathway- and cell-specific fashion.
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页码:2585 / 2597
页数:13
相关论文
共 58 条
[1]   AROMATIZATION OF ANDROSTENEDIONE BY HUMAN ADIPOSE-TISSUE STROMAL CELLS IN MONOLAYER-CULTURE [J].
ACKERMAN, GE ;
SMITH, ME ;
MENDELSON, CR ;
MACDONALD, PC ;
SIMPSON, ER .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1981, 53 (02) :412-417
[2]   Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients [J].
Agarwal, VR ;
Bulun, SE ;
Leitch, M ;
Rohrich, R ;
Simpson, ER .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (11) :3843-3849
[3]  
Baum M, 2002, LANCET, V359, P2131
[4]  
BOFFA LC, 1981, J BIOL CHEM, V256, P9612
[5]   Regulation of aromatase expression in estrogen-responsive breast and uterine disease: From bench to treatment [J].
Bulun, SE ;
Lin, ZH ;
Imir, G ;
Amin, S ;
Demura, M ;
Yilmaz, B ;
Martin, R ;
Utsunomiya, H ;
Thung, S ;
Gurates, B ;
Tamura, M ;
Langoi, D ;
Deb, S .
PHARMACOLOGICAL REVIEWS, 2005, 57 (03) :359-383
[6]   A LINK BETWEEN BREAST-CANCER AND LOCAL ESTROGEN BIOSYNTHESIS SUGGESTED BY QUANTIFICATION OF BREAST ADIPOSE-TISSUE AROMATASE CYTOCHROME-P450 TRANSCRIPTS USING COMPETITIVE POLYMERASE CHAIN-REACTION AFTER REVERSE TRANSCRIPTION [J].
BULUN, SE ;
PRICE, TM ;
AITKEN, J ;
MAHENDROO, MS ;
SIMPSON, ER .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1993, 77 (06) :1622-1628
[7]   USE OF TISSUE-SPECIFIC PROMOTERS IN THE REGULATION OF AROMATASE CYTOCHROME-P450 GENE-EXPRESSION IN HUMAN TESTICULAR AND OVARIAN SEX CORD TUMORS, AS WELL AS IN NORMAL FETAL AND ADULT GONADS [J].
BULUN, SE ;
ROSENTHAL, IM ;
BRODIE, AMH ;
INKSTER, SE ;
ZELLER, WP ;
DIGEORGE, AM ;
FRASIER, SD ;
KILGORE, MW ;
SIMPSON, AER .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1993, 77 (06) :1616-1621
[8]   Recruitment of CREB binding protein is sufficient for CREB-mediated gene activation [J].
Cardinaux, JR ;
Notis, JC ;
Zhang, QH ;
Vo, N ;
Craig, JC ;
Fass, DM ;
Brennan, RG ;
Goodman, RH .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (05) :1546-1552
[9]   AROMATASE-ACTIVITY OF MEMBRANE-FRACTIONS OF HUMAN ADIPOSE-TISSUE STROMAL CELLS AND ADIPOCYTES [J].
CLELAND, WH ;
MENDELSON, CR ;
SIMPSON, ER .
ENDOCRINOLOGY, 1983, 113 (06) :2155-2160
[10]   A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer [J].
Coombes, RC ;
Hall, E ;
Gibson, LJ ;
Paridaens, R ;
Jassem, J ;
Delozier, T ;
Jones, SE ;
Alvarez, I ;
Bertelli, G ;
Ortmann, O ;
Coates, AS ;
Bajetta, E ;
Dodwell, D ;
Coleman, RE ;
Fallowfield, LJ ;
Mickiewicz, E ;
Andersen, J ;
Lonning, PE ;
Cocconi, G ;
Stewart, A ;
Stuart, N ;
Snowdon, CF ;
Carpentieri, M ;
Massimini, G ;
Bliss, JM .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (11) :1081-1092