Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) Promotes Growth and Survival of Breast Epithelial Cells: Novel Regulation of the Estrogen Receptor

• Published in: Endocrinology (Philadelphia) 2013-05, Vol.154 (5), p.1780-1793
• Main Authors: Foulstone, Emily J, Zeng, Li, Perks, Claire M, Holly, Jeff M. P
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic drugs; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell activation; Cell death; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Chemotherapy; Chromosome 10; Drug Evaluation, Preclinical; Epithelial cells; Epithelium; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Growth factors; Humans; Insulin-Like Growth Factor Binding Protein 2 - antagonists & inhibitors; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-Like Growth Factor Binding Protein 2 - physiology; Insulin-like growth factor I; Insulin-like growth factor II; Insulin-like growth factor-binding protein 2; Insulin-like growth factors; Kinases; Malignancy; Mammary Glands, Human - drug effects; Mammary Glands, Human - metabolism; Mammary Glands, Human - physiology; Mortality; mRNA; Proteins; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptors; RNA, Small Interfering - pharmacology; Survival; Survival factor; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2012-1970

In breast tumors IGF binding protein-2 (IGFBP-2) is elevated, and the presence of IGFBP-2 has been shown to correlate with malignancy. However, how IGFBP-2 contributes to the malignant state is still unclear. Silencing IGFBP-2 blocked cell proliferation and in MCF-7 cells increased cell death, indicating that IGFBP-2 was acting in both a mitogenic and a survival capacity. Exogenous IGFBP-2 acting via integrin receptors to reduce phosphatase and tensin homolog deleted from chromosome 10 (PTEN) levels protected these cells against death induced by various chemotherapeutic agents. This was dependent on a functional estrogen receptor (ER)-α because silencing ER-α blocked the ability of IGFBP-2 to confer cell survival. Loss of IGFBP-2 increased levels of PTEN and improved chemosensitivity of the cells, confirming its role as a survival factor. Silencing IGFBP-2 had no effect on the response to IGF-II, but responses to estrogen and tamoxifen were no longer observed due to loss of ER-α, which could be prevented by the inhibition of PTEN. Conversely, exogenous IGFBP-2 increased ER-α mRNA and protein in both normal and cancer cells via its interaction with integrin receptors. These actions of IGFBP-2 on ER-α involved the IGF-I receptor and activation of phosphatidylinositol 3-kinase in the cancer cells but were independent of this in normal breast cells. The production of IGFBP-2 by breast cancer cells enhances their proliferative potential, increases their survival, and protects them against chemotherapy-induced death. IGFBP-2 not only modulates IGFs and directly regulates PTEN but also has a role in maintaining ER-α expression.