Role of the insulin-like growth factor system on an estrogen-dependent cancer phenotype in the MCF-7 human breast cancer cell line.
We previously established that exposure of the estrogen receptor (ER) alpha positive MCF-7 human breast cancer cell line to 17-beta-estradiol (E2) results in the post-confluent development of multilayered cellular aggregates (foci) which is consistent with the in vivo cancer phenotype of uncontrolled cellular proliferation. In this investigation, the interaction between the insulin-like growth factor receptor (IGF-IR) and ER-signaling systems in regard to post-confluent focus development was studied. We demonstrated that focus development requires the presence of E2 and insulin-like growth factor I (IGF-I) or insulin-like growth factor II (IGF-II), as well as intact ER and IGF-IR. Focus development in MCF-7 cultures, which occurs only after formation of a confluent monolayer, coincides with E2 regulation of key members of the IGF-signaling system such as IGF-IR, IGF-II, insulin receptor substrate 1 (IRS-1), and insulin-like growth factor binding protein 3 (IGFBP-3), as demonstrated by real-time polymerase chain reaction (PCR). To establish the relevancy of an intact IGF-signaling system for foci formation, we generated stable clones from MCF-7 with IGF-IR suppressed by siRNA. Results from these studies implicate signaling through the IGF-IR to be an integral requirement for E2-dependent post-confluent proliferation and focus formation. In summary, these studies establish the interactive roles of IGFs and E2 in the post-confluent development of foci, and will allow subsequent identification of targets for therapeutic intervention in the control and treatment of estrogen-dependent breast cancer.
Bradley
Laurie M
LM
Department of Environmental Health and Toxicology, School of Public Health, State University at Albany, Albany, NY, USA.
Gierthy
John F
JF
Pentecost
Brian T
BT
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*
D017931:DNA Primers; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D013002:Somatomedins; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1