Breast Cancer Awareness: High Levels of Hsp90 Cochaperone p23 Promote Tumor Progression and Poor Prognosis in Breast Cancer by Increasing Lymph Node Metastases and Drug Resistance

High Levels of Hsp90 Cochaperone p23 Promote Tumor Progression and Poor Prognosis in Breast Cancer by Increasing Lymph Node Metastases and Drug Resistance — Cancer Res

Skip to main page content

Home OnlineFirst Current Issue Past Issues Subscriptions Alerts Feedback AACR Publications AACR Home Search GO Advanced Search User Name Password Sign In

High Levels of Hsp90 Cochaperone p23 Promote Tumor Progression and Poor Prognosis in Breast Cancer by Increasing Lymph Node Metastases and Drug Resistance Natalie E. Simpson 1, W. Marcus Lambert 2, Renecia Watkins 2, Shah Giashuddin 5, S. Joseph Huang 6, Ellinor Oxelmark 2, Rezina Arju 2, Tsivia Hochman 3, Judith D. Goldberg 3, Robert J. Schneider 2, Luiz Fernando Lima Reiz 7, Fernando Augusto Soares 8, Susan K. Logan 1,4, and Michael J. Garabedian 2,4

Authors' Affiliations: Departments of 1Pharmacology, 2Microbiology, 3Environmental Medicine, and 4Urology, and NYU Cancer Institute, NYU School of Medicine, and 5Department of Medicine, New York Hospital Queens and Weill Cornell Medical College, New York, New York; 6Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; 7Instituto de ensino e pesquisa, Hospital Sirio Libanes, and 8Department of Anatomic Pathology, Hospital AC Camargo, Sao Paulo, SP, Brazil Corresponding Author:
Michael J. Garabedian, Department of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-7662; Fax: 212-263-8276; E-mail: michael.garabedian{at}nyumc.org. Abstract p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. Cancer Res; 70(21); 8446–56. ©2010 AACR.

Footnotes Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).