title: Growth hormone potentiates 17β-estradiol-dependent breast cancer cell proliferation independently of IGF-I receptor signaling.
abstract: Estrogen action in mammary gland development and breast cancer progression is tightly linked to the GH/IGF-I axis. Although many of the effects of GH on mammary gland growth and development require IGF-I, the extent to which GH action in breast cancer depends on IGF-I is not known. We examined GH action in a panel of estrogen receptor-positive breast cancer cell lines and found that T47D cells express significant levels of GH receptor and that GH significantly enhances 17β-estradiol (E2)-stimulated proliferation in these cells. GH action in the T47D cells was independent of changes in IGF-I and IGF-I receptor (IGF-IR) expression and IGF-IR signaling, suggesting that GH can exert direct effects on breast cancer cells. Although E2-dependent proliferation required IGF-IR signaling, the combination of GH+E2 overcame inhibition of IGF-IR activity to restore proliferation. In contrast, GH required both Janus kinase 2 and epidermal growth factor receptor signaling for subsequent ERK activation and potentiation of E2-dependent proliferation. Downstream of these pathways, we identified a number of immediate early-response genes associated with proliferation that are rapidly and robustly up-regulated by GH. These findings demonstrate that GH can have important effects in breast cancer cells that are distinct from IGF-IR activity, suggesting that novel drugs or improved combination therapies targeting estrogen receptor and the GH/IGF axis may be beneficial for breast cancer patients.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 South Wolcott Avenue, MC 901, Chicago, Illinois 60612, USA.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Felice
authors.forename: Lamiaa
authors.initials: L
authors.lastname: El-Shennawy
authors.forename: Shuangping
authors.initials: S
authors.lastname: Zhao
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Lantvit
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C583557:IGF1 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; C507924:JAK2 protein, human; D053614:Janus Kinase 2