ERE-independent ERalpha target genes differentially expressed in human breast tumors.
The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERalpha can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-kappaB) at their cognate sites on DNA. We previously generated a mutant form of ERalpha (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERalpha into MDA-MB231 ERalpha-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17beta-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERalpha pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERalpha responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERalpha pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERalpha target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.
Glidewell-Kenney
Christine
C
Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern University, Feinberg School of Medicine, 251 E. Huron Street, Galter Pavilion Suite 3-150, Chicago, IL 60611, USA.
Weiss
Jeffrey
J
Lee
Eun-Jig
EJ
Pillai
Suresh
S
Ishikawa
Toshio
T
Ariazi
Eric A
EA
Jameson
J Larry
JL
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004273:DNA, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects; D020218:Response Elements / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D004967:Estrogens; D014157:Transcription Factors; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol