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 17ß-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.
Subject(s)
Breast Neoplasms/metabolism , Estradiol/metabolism , Human Growth Hormone/metabolism , Insulin-Like Growth Factor I/metabolism , Receptor, IGF Type 1/metabolism , Receptors, Somatotropin/metabolism , Signal Transduction , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Human Growth Hormone/genetics , Humans , Insulin-Like Growth Factor I/antagonists & inhibitors , Insulin-Like Growth Factor I/genetics , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , MAP Kinase Signaling System/drug effects , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Receptors, Somatotropin/genetics , Recombinant Proteins/metabolism , Signal Transduction/drug effects , Up-Regulation/drug effectsABSTRACT
Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i6A-) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)/Tag]. The resulting bigenic animals (i6A-/Tag) and control WT/Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.
