IKKbeta mediates cell shape-induced aromatase expression and estrogen biosynthesis in adipose stromal cells.
Aromatase (Cyp19) is a key enzyme in estrogen biosynthesis and an important target in breast cancer therapy. Within tumor microenvironment, tumor cells stimulate aromatase expression in adipose stromal cells (ASCs), which in turn promotes estrogen-dependent growth of estrogen receptor (ER)-positive tumor cells. However, it is not clear how aromatase transcription and estrogen biosynthesis are regulated in ASCs under a precancerous condition. Here we demonstrate that cell shape change alone is sufficient to induce aromatase expression in primary ASCs from cancer-free individuals. The activation of aromatase transcription is mediated by IkappaB kinase-beta (IKKbeta), a kinase previously known for its cancer-promoting activity in tumor cells. Activation of IKKbeta leads to elevated expression of transcription factor CCAAT/enhancer-binding protein-beta (C/EBPbeta), which binds to and stimulates two breast cancer-associated promoters of the aromatase gene. We also show that shape-induced estrogen production in ASCs can stimulate estrogen-dependent transcription in ER-positive breast tumor cells. We suggest that IKKbeta-dependent aromatase induction due to changes in cellular architecture in adipose tissue may contribute to the breast cancer risks associated with high mammagraphic density and obesity.
Ghosh
Sagar
S
Department of Molecular Medicine, Institute of Biotechnology, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Choudary
Ahsan
A
Ghosh
Sangeeta
S
Musi
Nicolas
N
Hu
Yanfen
Y
Li
Rong
R
D000273:Adipose Tissue / Q000166:cytology* / Q000187:drug effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004967:Estrogens / Q000096:biosynthesis*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D016086:Lentivirus; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004967:Estrogens; D009570:Nitriles; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D012717:Sesquiterpenes; D013450:Sulfones; C002669:parthenolide; D001141:Aromatase; D051550:I-kappa B Kinase