Diane M. Robins, Ph.D.
Professor of Human Genetics, Research Scientist for Reproductive Sciences Program
We study gene regulation by steroid hormones, focusing on transcriptional mechanisms, hormone-dependent cancers, and sex-dependent gene modulation. Steroid receptors are ligand-activated transcription factors with diverse functions, yet several act via common DNA binding sites and interact with common coregulators. We examine how specific gene control is attained by the androgen receptor (AR).
To study the central role of AR in prostate cancer and to model human disease, we converted the mouse gene to the human sequence (humanized AR mice). Variant hAR alleles in mice confer differences in cancer initiation, progression, and response to therapy. This allows us to study mechanisms of treatment resistance, particularly by somatic AR mutation. In both mouse and human tumors, AR mutants use diverse mechanisms to evade therapy. We are using Next Generation Sequencing to profile differential gene expression and alternative regulatory networks, to improve prognosis and anti-AR treatments.
Sex differences in gene expression occur widely, impacting physiology and incidence of many diseases. We identified via mutant mice a KRAB zinc finger repressor (Regulator-of-sex-limitation) that influences sex-biased expression in liver of genes acting in lipid and steroid metabolism. Rsl deficiency leads to early puberty, lack of dietary stress response and susceptibility to obesity and diabetes. Rsl provides insight into KRAB-ZFP epigenetic mechanisms as well as evolution of this recently expanded gene family.
Robins DM: (2011) Androgen receptor gene polymorphisms and alterations in prostate cancer: of humanized mice and men. Molecular and Cellular Endocrinology (epub ahead of print).
Simanainen U, Brogley M, Gao YR, Jimenez M, Harwood DT, Handelsman DJ, Robins DM: (2011) Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo. Molecular and Cellular Endocrinology 7: 81-86.
Krebs CJ, Robins DM: (2010) A pair of mouse KRAB zinc finger proteins modulates multiple indicators of female reproduction. Biology of Reproduction 82: 662-668.
Yu Z, Wang AM, Robins DM, Lieberman AP: (2009) Altered RNA splicing contributes to skeletal muscle pathology in Kennedy disease knock-in mice. Disease Models and Mechanisms 2: 500-7.
Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, LaPensee E, Dhanasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA, Pienta KJ, Robins DM: (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Research 69:4434-4442.
Krebs CJ, Khan S, MacDonald JW, Sorenson M, Robins DM: (2009) The regulator of sex-limitation (Rsl) KRAB zinc finger proteins modulate sex-dependent and -independent liver metabolism. Physiological Genomics 38: 16-28.
O'Mahony OA, Steinkamp MP, Albertelli MA, Brogley M, Rehman H, Robins DM: (2008) Profiling human androgen receptor mutations reveals treatment effects in a mouse model of prostate cancer. Molecular Cancer Research 6: 1691-1701.
Albertelli MA, O'Mahony OA, Brogley M, Tosoian J, Steinkamp M, Daigneault S, Wojno K, Robins DM: (2008) Glutamine tract length of human androgen receptors affects both androgen-dependent and -independent prostate cancer in mice. Human Molecular Genetics 17: 98-110.
Lieberman AP, Robins DM: (2008) The androgen receptor's CAG/glutamine tract in mouse models of neurological disease and cancer. Journal of Alzheimer's Disease 14: 247-55.
Yu Z, Dadgar N, Albertelli MA, Gruis K, Jordan C, Robins DM, Lieberman AP: (2006) Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. Journal of Clinical Investigation 116: 2663-72.
Albertelli MA, Scheller A, Brogley M, Robins DM: (2006) Replacing the mouse androgen receptor with human alleles demonstrates glutamine tract length dependent effects on physiology and tumorigenesis in mice. Molecular Endocrinology, 20:1248-1260.
Krebs CJ, Larkins LK, Khan SM, Robins DM: (2005) Expansion and diversification of KRAB zinc-finger genes within a cluster including Regulator of sex-limitation 1 and 2. Genomics 85: 752-761
Krebs CJ, Larkins LK, Price R, Tullis KM, Miller RD, Robins DM: (2003) Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression. GenesDev. 17: 2664-2674.
Gonzalez MI, Robins DM: (2001) OCT-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of the coactivator SRC-1. J. Biol. Chem. 276: 6420-8.