High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.
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.
Simpson
Natalie E
NE
Department of Pharmacology, and NYU Cancer Institute, NYU School of Medicine, New York, New York 10016, USA.
Lambert
W Marcus
WM
Watkins
Renecia
R
Giashuddin
Shah
S
Huang
S Joseph
SJ
Oxelmark
Ellinor
E
Arju
Rezina
R
Hochman
Tsivia
T
Goldberg
Judith D
JD
Schneider
Robert J
RJ
Reiz
Luiz Fernando Lima
LF
Soares
Fernando Augusto
FA
Logan
Susan K
SK
Garabedian
Michael J
MJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008207:Lymphatic Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D000071876:Prostaglandin-E Synthases; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004967:Estrogens; D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D051057:Proto-Oncogene Proteins c-akt; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases