ChristopherC Williams, PhD
Professor and Chair,Division of Basic Pharmaceutical Sciences
Xavier Co-Director forOXIHER
Xavier University ofLouisiana, College of Pharmacy
Targeting nuclear receptor signaling in the management ofbreast cancer
Indirecttargeting of ERα activity in BCa. Tamoxifen has remaineda mainstay therapy for the treatment of ER (+) breast cancer (BCa),particularly in premenopausal women. However, a significant number of patients presentwith either de novo or acquired resistance to tamoxifen. In addition, tamoxifenexhibits mitogenic effects on the endometrium, and increases the potential forendometrial cancer. One mechanism that may play a central role in thetherapeutic failure of tamoxifen in the breast and in promoting its mitogeniceffects in the uterus is through the expression of the 36kD truncated isoformof the receptor, ERα36. Since ERα36 activity is enhanced by antagonists to fulllength ERα, inhibition through traditional antagonism of the ligand bindingdomain is unlikely to be effective. As such we propose targeting both ERαvariants indirectly by inhibiting kinases responsible for phosphorylation ofthe receptors. Successful implementation of this strategy would provideeffective therapeutics tools to treat both de novo and acquired tamoxifenresistance in breast cancer.
Prognostic significance of NURR1 in BCa. Estrogen receptor α (ERα) expression is typically regardedas a favorable prognostic indicator in BCa, however a significant proportion of ERα (+) patients stillexperience either de novo or acquired resistance to endocrine therapies. Wehave shown that the loss of orphan nuclear receptor NURR1 expression isassociated with neoplastic transformation of the breast epithelium and shorterrelapse-free survival (RFS) among systemically treated breast cancer (BCa)patients. Additionally, we have demonstrated that the prognostic significanceof NURR1 is particularly robust among Black womenwith luminal A BCa. Furthermore, we found that NURR1 expression is positivelycorrelated with Oncotype Dx marker for estrogen responsiveness, but negativelycorrelated to markers of proliferation. Our goal is to further to develop NURR1as prognostic biomarker for endocrine responsiveness, and to develop strategiesto pharmacological impact NURR1 activity in BCa. Successful completion of thesestudies will provide a new level of patient stratification that will be predictiveof endocrine-responsiveness and may provide a druggable target for thetreatment of BCa.
MyNCBILink
https://www.ncbi.nlm.nih.gov/myncbi/christopher.williams.1/bibliography/public/
SelectedPublications
Walker RR,Patel JR, Gupta A, Davidson AM, Williams CC, Payton-Stewart F, Boué SM, BurowME, Khupse R, Tilghman SL. Glyceollins Trigger Anti-Proliferative Effects inHormone-Dependent Aromatase-Inhibitor-Resistant Breast Cancer Cells through theInduction of Apoptosis. Int J Mol Sci. 2022 Mar 7;23(5). doi:10.3390/ijms23052887. PubMed PMID: 35270029; PubMed Central PMCID: PMC8911299.
Frazier T,Williams C, Henderson M, Duplessis T, Rogers E, Wu X, Hamel K, Martin EC,Mohiuddin O, Shaik S, Devireddy R, Rowan BG, Hayes DJ, Gimble JM. Breast CancerReconstruction: Design Criteria for a Humanized Microphysiological System.Tissue Eng Part A. 2021 Apr;27(7-8):479-488. doi: 10.1089/ten.TEA.2020.0372.Epub 2021 Mar 10. PubMed PMID: 33528293; PubMed Central PMCID: PMC8196546.
McCarthy M,Brown T, Alarcon A, Williams C, Wu X, Abbott RD, Gimble J, Frazier T.Fat-On-A-Chip Models for Research and Discovery in Obesity and Its MetabolicComorbidities. Tissue Eng Part B Rev. 2020 Dec;26(6):586-595. doi:10.1089/ten.TEB.2019.0261. Epub 2020 Dec 3. Review. PubMed PMID: 32216545;PubMed Central PMCID: PMC8196547.
Bender R,McCarthy M, Brown T, Bukowska J, Smith S, Abbott RD, Kaplan DL, Williams C,Wade JW, Alarcon A, Wu X, Lau F, Gimble JM, Frazier T. Human Adipose DerivedCells in Two- and Three-Dimensional Cultures: Functional Validation of an InVitro Fat Construct. Stem Cells Int. 2020;2020:4242130. doi:10.1155/2020/4242130. eCollection 2020. PubMed PMID: 32587620; PubMed CentralPMCID: PMC7303735.
Schexnayder C,Broussard K, Onuaguluchi D, Poché A, Ismail M, McAtee L, Llopis S, KeizerweerdA, McFerrin H, Williams C. Metformin Inhibits Migration and Invasion bySuppressing ROS Production and COX2 Expression in MDA-MB-231 Breast CancerCells. Int J Mol Sci. 2018 Nov 21;19(11). doi: 10.3390/ijms19113692. PubMedPMID: 30469399; PubMed Central PMCID: PMC6274682.
Carriere PP,Llopis SD, Naiki AC, Nguyen G, Phan T, Nguyen MM, Preyan LC, Yearby L, Pratt J,Burks H, Davenport IR, Nguyen TA, Parker-Lemieux K, Payton-Stewart F, WilliamsCC, Boué SM, Burow ME, Collins-Burow B, Hilliard A, Davidson AM, Tilghman SL.Glyceollin I Reverses Epithelial to Mesenchymal Transition in LetrozoleResistant Breast Cancer through ZEB1. Int J Environ Res Public Health. 2015 Dec22;13(1):ijerph13010010. doi: 10.3390/ijerph13010010. PubMed PMID: 26703648;PubMed Central PMCID: PMC4730401.
Williams MD,Nguyen T, Carriere PP, Tilghman SL, Williams C. Protein Kinase CK2 ExpressionPredicts Relapse Survival in ERα Dependent Breast Cancer, and Modulates ERαExpression in Vitro. Int J Environ Res Public Health. 2015 Dec22;13(1):ijerph13010036. doi: 10.3390/ijerph13010036. PubMed PMID: 26703694;PubMed Central PMCID: PMC4730427.
Tilghman SL,Townley I, Zhong Q, Carriere PP, Zou J, Llopis SD, Preyan LC, Williams CC,Skripnikova E, Bratton MR, Zhang Q, Wang G. Proteomic signatures of acquiredletrozole resistance in breast cancer: suppressed estrogen signaling andincreased cell motility and invasiveness. Mol Cell Proteomics. 2013Sep;12(9):2440-55. doi: 10.1074/mcp.M112.023861. Epub 2013 May 23. PubMed PMID:23704778; PubMed Central PMCID: PMC3769322.
Llopis S,Singleton B, Duplessis T, Carrier L, Rowan B, Williams C. Dichotomous roles forthe orphan nuclear receptor NURR1 in breast cancer. BMC Cancer. 2013 Mar21;13:139. doi: 10.1186/1471-2407-13-139. PubMed PMID: 23517088; PubMed CentralPMCID: PMC3617898.
Williams CC,Singleton BA, Llopis SD, Skripnikova EV. Metformin induces asenescence-associated gene signature in breast cancer cells. J Health Care PoorUnderserved. 2013 Feb;24(1 Suppl):93-103. doi: 10.1353/hpu.2013.0044. PubMedPMID: 23395946; PubMed Central PMCID: PMC3680098.
Huderson BP,Duplessis TT, Williams CC, Seger HC, Marsden CG, Pouey KJ, Hill SM, Rowan BG.Stable inhibition of specific estrogen receptor α (ERα) phosphorylation confersincreased growth, migration/invasion, and disruption of estradiol signaling inMCF-7 breast cancer cells. Endocrinology. 2012 Sep;153(9):4144-59. doi:10.1210/en.2011-2001. Epub 2012 Jun 25. PubMed PMID: 22733972; PubMed CentralPMCID: PMC3423624.
Duplessis TT,Williams CC, Hill SM, Rowan BG. Phosphorylation of Estrogen Receptor α atserine 118 directs recruitment of promoter complexes and gene-specifictranscription. Endocrinology. 2011 Jun;152(6):2517-26. doi:10.1210/en.2010-1281. Epub 2011 Apr 19. PubMed PMID: 21505052; PubMed CentralPMCID: PMC3100622.
Heard M,Maina CV, Morehead BE, Hoener MC, Nguyen TQ, Williams CC, Rowan BG,Gissendanner CR. A functional NR4A nuclear receptor DNA-binding domain isrequired for organ development in Caenorhabditis elegans. Genesis. 2010Aug;48(8):485-91. doi: 10.1002/dvg.20646. PubMed PMID: 20506374; PubMed CentralPMCID: PMC2927863.
Williams CC,Basu A, El-Gharbawy A, Carrier LM, Smith CL, Rowan BG. Identification of fournovel phosphorylation sites in estrogen receptor alpha: impact onreceptor-dependent gene expression and phosphorylation by protein kinase CK2.BMC Biochem. 2009 Dec 31;10:36. doi: 10.1186/1471-2091-10-36. PubMed PMID:20043841; PubMed Central PMCID: PMC2811108.
Skliris GP,Rowan BG, Al-Dhaheri M, Williams C, Troup S, Begic S, Parisien M, Watson PH,Murphy LC. Immunohistochemical validation of multiple phospho-specific epitopesfor estrogen receptor alpha (ERalpha) in tissue microarrays of ERalpha positivehuman breast carcinomas. Breast Cancer Res Treat. 2009 Dec;118(3):443-53. doi:10.1007/s10549-008-0267-z. Epub 2008 Dec 23. PubMed PMID: 19104930; PubMedCentral PMCID: PMC3448371.
Zhu Y,Sullivan LL, Nair SS, Williams CC, Pandey AK, Marrero L, Vadlamudi RK, JonesFE. Coregulation of estrogen receptor by ERBB4/HER4 establishes agrowth-promoting autocrine signal in breast tumor cells. Cancer Res. 2006 Aug15;66(16):7991-8. doi: 10.1158/0008-5472.CAN-05-4397. PubMed PMID: 16912174
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Clark DE,Williams CC, Duplessis TT, Moring KL, Notwick AR, Long W, Lane WS, Beuvink I,Hynes NE, Jones FE. ERBB4/HER4 potentiates STAT5A transcriptional activity byregulating novel STAT5A serine phosphorylation events. J Biol Chem. 2005 Jun24;280(25):24175-80. doi: 10.1074/jbc.M414044200. Epub 2005 Apr 29. PubMedPMID: 15863494.
Williams CC,Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE. The ERBB4/HER4receptor tyrosine kinase regulates gene expression by functioning as a STAT5Anuclear chaperone. J Cell Biol. 2004 Nov 8;167(3):469-78. doi:10.1083/jcb.200403155. PubMed PMID: 15534001; PubMed Central PMCID: PMC2172499.
NURR1 IsDifferentially Expressed in Breast Cancer According to Patient Racial Identityand Tumor Subtype. BioMedInformatics. NIHMSID: NIHMS1899970.
Key words: Breast Cancer, Nuclear Receptor, Estrogen, NURR1, NR4A2, Kinase, CK2, Posttranslational modification
