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.