314d Roger Adams Lab
Office: (217) 333-1788
Lab: (217) 244-0207
Fax: (217) 244-5858
Mail to: Department of Biochemistry
419 Roger Adams Lab.
University of Illinois
600 S. Mathews Avenue
Urbana, IL 61801
David J Shapiro
Professor of Biochemistry
Chromatin Structure, Drug Discovery, Endocrinology, Protein-Nucleic Acid Interactions, Receptor Biochemistry, Regulation of Gene Expression, Signal Transduction
B.S. 1967 Brooklyn College
Ph.D. 1972 Purdue University
Postdoc. 1972-1973 Stanford University Medical School, 1973-1974 Stanford University
Identification and use of novel small molecule biomodulators to identify and analyze pathways important in cancer and development of these small molecules as potential anticancer drugs.
Small molecule biomodulators for studying and treating cancer
Our previous research focused on mechanisms of steroid receptor action at the transcriptional and posttranscriptional levels. With our extensive experience in steroid hormone receptor action, it was possible to leverage these skills and develop powerful high throughput screening platforms for identifying small molecule modulators of steroid hormone receptor action.
In calendar year 2012, we described novel small molecule inhibitors of androgen receptor (AR) (Cherian, M., et al., 2012), estrogen receptor (ER) (Andruska, N., et al., 2012) and progesterone receptor (PR) (Aninye, I., et al., 2012). These small molecules are new probes for key pathways in prostate cancer, and breast, ovarian and endometrial cancer, and are being evaluated as potential anticancer drugs.
Estrogen and androgen receptor action in cancer
Steroid hormones, such as estrogens, testosterone and other androgens, exert their biological activity by binding to specific receptor proteins called steroid/nuclear receptors. In the nucleus, these receptors regulate the expression of specific genes. The estrogen and androgen receptors (ER) and (AR) are unique among the ~45 nuclear receptors in that they stimulate cell proliferation. Estrogens, acting through the ER, are implicated in the growth and metastases of breast, ovarian, endometrial and lung cancers. Testosterone, acting through the AR, plays a key role in growth of both primary and recurrent prostate cancers. Treatment of breast and prostate cancer involves inhibiting hormone production and the use of small molecules that compete with the normal hormones for binding to the receptor. Over time the tumors become resistant to these therapies and growth resumes with few therapeutic options. An important goal of our research is to identify new small molecule inhibitors that bypass the sites targeted by current drugs and are effective against tumors that are resistant to current therapies. For example, the most common mechanism by which prostate cancers become resistant to the widely used drug Casodex is overproduction of AR. When AR levels are high Casodex acts as an androgen and stimulates tumor growth. Our new AR inhibitor, CPIC (Cherian, M. et al., 2012), acts in a different way than Casodex and retains the ability to block AR action when AR levels are high. CPIC effectively inhibits actions of AR that are resistant to both current and experimental therapeutics.
Using small molecules to identify new pathways and critical interactions
The wealth of available information makes it difficult to determine which interactions and pathways are actually important in a cell. For example, with more than 400 known ER coregulator proteins and ER binding to more than 10,000 sites in the human genome, its quite challenging to sort through this massive ER interactome and identify those interactions critical to specific actions of ER. Our approach to identifying what’s important is to “ask the cell”. Our unbiased cell-based high throughput screen (Andruska et al., 2012) can identify any small molecule whose actions result in reduced activation of transcription by estrogen receptor. So we are interrogating the cell and asking the cell to identify pathway targetable by small molecules that results in reduced transcription by estrogen receptor. Confirming the potential of this novel strategy, the small molecule ER inhibitor we identified as most promising for potential anti-cancer drug development stops the growth of ER containing breast, ovarian and endometrial containing cancer cells primarily by targeting a pathway not previously linked to ER action. This finding validates use of our small molecule strategy for identification of novel pathways and interactions.
For background and more details see our Web site at www.life.uiuc.edu/shapiro . This site is accessible through the Lab Page link and in the Department of Biochemistry Web site.
Cherian MT, Wilson EM and Shapiro DJ (2012) A competitive inhibitor that reduces recruitment of androgen receptor to androgen responsive genes. J. Biol. Chem. 287: 23368-23380
Andruska N, Mao C, Cherian M, Zhang C and Shapiro DJ (2012) Evaluation of a luciferase-based reporter assay for inhibitors of estrogen receptor α-action as a screen for inhibitors of estrogen-ERα-induced proliferation of breast cancer cells. J. Biomolecular Screening, 17(7): 921-932 PMID 22498909.
Zhang C, Nordeen SK and Shapiro DJ (2012) Fluorescence anisotropy microplate assay to investigate the interaction of full-length steroid receptor coactivator-1a with steroid receptors. Methods in Molecular Biology, (M. Binou Ed.) Springer, In press.
Aninye IO, Berg KC, Mollo AR, Nordeen SK, Wilson, EM, and Shapiro DJ (2012) 8-Alkylthio-6-thio-substitited theophyllene analogues as selective noncompetitive progesterone receptor antagonists, Steroids, 77: 596-601. PMID 22421057.
Huang, B, Qu, Z, Ong CW, Tsang N, Xiao G., Shapiro DJ, Salto-Tellez M, Ito K, Chen L-F (2012) RUNX3 acts as a tumor supressor in breast cancer by targeting estrogen receptor alpha. Oncogene, 37:527-534. PMID 21706501.
Shapiro, DJ, Mao C and Cherian MT (2011) Small molecule inhibitors as probes for estrogen and androgen receptor action. J. Biol. Chem. 286:4043-4048 PMCID: 3039394
Woo H-H, Yi X, Lamb T, Menzl L, Baker T, Shapiro DJ, Chambers SK (2011) Posttransriptional suppression of protoconcogene c-fms by vigilin in breast cancer. Mol. Cell Biol. 31: 215-225. PMCID: 3019847
Kretzer NM, Cherian M, Mao. C, Aninye I, Reynolds P, Schiff R, Hergenrother PJ, Nordeen SK, Wilson EM and Shapiro DJ (2010) A Non-competitive Small Molecule Inhibitor of Estrogen-regulated Gene Expression and Breast Cancer Cell Growth that Enhances Proteasome-dependent Degradation of Estrogen Receptor alpha. J. Biol. Chem. 285:41863-41873. PMCID: 3017855
Powell E, Wang Y, Shapiro DJ and Xu W (2010) Differential Requirements of Hsp90 and DNA for the Formation of Estrogen Receptor Homodimers. J. Biol. Chem. 285:16125-16134. PMCID: 2871481
Mao C, Pattterson NM, Cherian, MT, Aninye IO, Zhang C, Montoya JB, Cheng J, Putt KS, Hergenrother PJ, Wilson EM, Nardulli AM, Nordeen SK and Shapiro DJ 2008 A new small molecule inhibitor of estrogen receptor Α binding to estrogen response elements blocks estrogen-dependent growth of cancer cells. J Biol Chem., 283: 12819- 12830. Online: jbc.org/cgi/content/full/279/6/5025
Jiang X, Ellison SJ, Alarid, ET and Shapiro DJ 2007 Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene, 26: 4106-4114 Online: nature.com/onc/journal/v26/n28/full/1210197a
Cunningham TD, Jiang X and Shapiro, DJ 2007 Expression of high levels of human proteinase inhibitor 9 blocks both perforin/granzyme and Fas/Fas ligand-mediated cytotoxicity. Cellular Immunology, 245:32-41.
Wang S, Zhang C, Nordeen SK, and Shapiro DJ 2007 In vitro fluorescence anisotropy analysis of the interaction of full-length SRC1a with estrogen receptors alpha and beta supports an active displacement model for coregulator utilization. J. Biol. Chem., 282:2765-2775. Online: jbc.org/cgi/content/full/282/5/2765
Cheng J, Zhang C, and Shapiro DJ 2008 A functional serine 118 phosphorylation site in estrogen receptor-Α is required for down-regulation of gene expression by 17β-estradiol and by 4-hydroxytamoxifen. Endocrinology, 148: 4634-4641. Online: endo.endojournals.org/cgi/content/full/148/10/4634
Zhou J-H, Yu DV, Cheng J, and Shapiro DJ 2007 Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen-induced cell death. Steroids, 72: 765-777. Online: sciencedirect.com/science/article/B6TC9-4P4NPK31/2/d95ac32e385f30ef684b4f8d6cbdbfd4
Cheng J, Yu DV, Zhou J-H and Shapiro DJ 2007 Tamoxifen induction of C/EBPΑ is required for tamoxifen-induced apoptosis. J. Biol. Chem. 282: 30535-30543 Online: jbc.org/cgi/doi/10.1074/jbc.M704829200