title: Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth.
abstract: Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Casa
authors.forename: Adam S
authors.initials: AS
authors.lastname: Potter
authors.forename: Simeen
authors.initials: S
authors.lastname: Malik
authors.forename: ZaWaunyka
authors.initials: Z
authors.lastname: Lazard
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.forename: Hee-Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Powell H
authors.initials: PH
authors.lastname: Brown
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D015536:Down-Regulation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011728:Pyridones / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C504983:BMS 536924; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011728:Pyridones; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1