Research in the Cohick laboratory focuses on the role of the insulin-like growth factor (IGF) system in normal mammary gland physiology as well as breast cancer. The IGFs are peptide growth factors that regulate cell proliferation, differentiation, survival and migration, processes critical to both normal mammary gland development and lactation as well as breast cancer tumorigenesis. They associate with a family of high affinity binding proteins (IGFBPs) that function to transport the IGFs in the circulation and prolong their half-life. In addition, IGFBPs act at the cellular level to either enhance or inhibit the biological actions of IGFs as well as many other agents that affect cell growth, survival and migration. It is now generally accepted that many of these effects are independent of binding to IGF, although the precise mechanisms are generally unknown.
Specific Research Areas
Physiological Role of IGF-I and IGFBP-3 in Cell Growth and Stress-induced Apoptosis
The mammary epithelial cell (MEC) is the cell type that produces milk. It is also the major site of origin of breast/mammary tumors. In a lactating animal, the number of epithelial cells in the gland at any one time determines the amount of milk produced. Therefore, understanding the factors that regulate MEC number will impact persistency of lactation. Work in our laboratory has shown that both the pro-growth factor IGF-I and the apoptotic stress factor anisomycin (ANS) increase the production of IGFBP-3, an IGFBP with both IGF-dependent as well as independent actions. We have found that these factors activate different intracellular signaling cascades to increase IGFBP-3 production. Using small interfering RNA technology, we have found that the loss of IGFBP-3 decreases the ability of IGF-I to increase growth and the ability of ANS to induce apoptosis. Why do factors with different biological outcomes upregulate the same molecule in the MEC? We propose that cellular localization plays a role in the biological action of IGFBP-3 within the cell and are currently testing this hypothesis.
Additional areas of interest in this area include the role of IGFBP-5 in regulating growth, differentiation and apoptosis of stromal fibroblasts and interactions between the stromal and epithelial compartments in the mammary gland that regulate these processes.
Role of in Utero Alcohol Exposure on Mammary Cancer Risk in Adulthood
Prenatal alcohol exposure can lead to fetal alcohol spectrum disorder (FASD), the most severe case being fetal alcohol syndrome (FAS). Each year in the US alone, approximately 1200 children are born with FAS. In addition to the devastating direct effects of FAS on development, data from our lab indicates that alcohol consumption during pregnancy increases susceptibility to carcinogen-induced mammary tumorigenesis in rat offspring. In addition, tumors from these offspring present with a more malignant phenotype (i.e. more adenocarcinomas and more estrogen-receptor negative tumors). Our studies show that the epithelial structure of the prepubertal mammary gland is more proliferative and shows alterations in the IGF/estradiol axis. Thus, women born to mothers who consume alcohol during pregnancy may be at increased risk of developing breast cancer as adults and they may develop breast cancer with a worse clinical outcome. We are currently investigating the role of the IGF and estradiol systems as well as potential epigenetic effects that may underlie this effect.
Mechanism of Action of Ricin in Mammalian Cells
Ricin is a ribosome inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. In collaboration with Dr. Nilgun Tumer in the Department of Plant Science and Pathology, we are studying the mechanisms by which this plant toxin kills mammalian cells. We have found that ricin induces apoptosis through the JNK signal transduction pathway, and that it can inhibit the unfolded protein response, a survival response that helps cells to recover from endoplasmic reticulum stress. We are presently constructing and analyzing mutants of RTA, the active component of the ricin molecule, to study how RTA interacts with the ribosome as well as intracellular signaling molecules to induce apoptosis.
Selected Representative Publications
- Polanco TA, Crismale-Gann C, Cohick WS. 2011. Exposure to Alcohol In Utero Leads to Enhanced Prepubertal Mammary Development and Alterations in Mammary IGF and Estradiol Systems. Hormones and Cancer Aug;2(4):239-48.
- Wang C-T, Jetzt, AE, Cheng J-S, Cohick WS. 2011. Inhibition of the Unfolded Protein Response by Ricin A-Chain Enhances Its Cytotoxicity in Mammalian Cells. Toxins 3(5), 453-468; doi:10.3390/toxins3050453.
- Polanco TA, Crismale-Gann C, Reuhl KR, Sarkar DK, Cohick WS. 2010. Fetal alcohol exposure increases mammary tumor susceptibility and alters tumor phenotype in rats. Alcoholism: Clinical and Experimental Research. Jul 21.34:1879-1887 PubMed
- Jetzt AE, Cheng JS, Tumer NE, Cohick WS. 2009. Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells. Intl J Biochem Cell Biol 41:2503-2510. PubMed
- Leibowitz BJ, Cohick WS. 2009. Endogenous IGFBP-3 is required for both growth factor-stimulated cell proliferation and cytokine-induced apoptosis in mammary epithelial cells. J Cell Physiol 220:182-188. PubMed
- Loor JJ, Cohick WS. 2009. ASAS centennial paper: Lactation biology for the twenty-first century. J Anim Sci 87(Feb):813-824. Epub 2008 Sept. 26. PubMed
- Fleming JM, Brandimarto JA, Cohick WS 2007 The mitogen-activated protein kinase pathway tonically inhibits both basal and IGF-stimulated IGF binding proten-5 production in mammary epithelial cells. J Endocrinol (June) 194:349-359.
- Fleming JM, Desury G, Polanco T, Cohick WS 2006 IGF-I and epidermal growth factor receptors recruit distinct upstream signaling molecules to enhance AKT activation in mammary epithelial cells. Endocrinology 147 (December):6027-6035.
- Thorn SR, Purup S, Cohick WS, Vestergaard M, Sejrsen K, Boisclair YR 2006 Leptin does not act directly on mammary epithelial cells in prepubertal dairy heifers. J Dairy Sci. 89 (May):1467-1477.
- Fleming JM, Leibowitz BJ, Kerr DE, Cohick WS. 2005 IGF-I differentially regulates IGF binding protein expression in primary mammary fibroblasts and epithelial cells. J Endocrinol 186:165-178.
- Sivaprasad U, Fleming J, Verma PS, Hogan KA, Desury G, Cohick WS. 2004 Stimulation of insulin-like growth factor (IGF) binding protein-3 synthesis by IGF-I and transforming growth factor-α is mediated by both phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways in mammary epithelial cells. Endocrinology 145:4213-4221.
- Cornwell T, Cohick WS, Raskin I. 2004 Dietary phytoestrogens and health. Phytochemistry 65:995-1016.
- Grill CJ, Sivaprasad U, Cohick WS. 2002 Constitutive expression of IGF binding protein-3 by mammary epithelial cells alters signaling through akt and p70S6 kinase. J Mol Endocrinol 29:153-162.
- Grill CJ, Cohick WS, Sherman A. 2001 Postnatal development of the rat mammary gland is preserved during iron deficiency. J Nutrition 131:1444-1448
- Cohick WS, Wang B, Verma P, Boisclair Y. 2000. Insulin-like growth factor-I and cyclic AMP regulate IGF binding protein-3 gene expression by transcriptional and post-transcriptional mechanisms in mammary epithelial cells. Endocrinology 4583-4591.
- Grill CJ, Cohick WS. 2000. Insulin-like growth factor binding protein-3 mediates IGF-I action in a bovine mammary epithelial cell line independent of an IGF interaction. J Cellular Physiology 183:273-283