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

Abstract

Abstractp23 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.

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

“…In summary, HSP90 has been linked to chemoresistance in different clinical settings including breast cancer [36][37][38][39][40][41].The described study of Song et al [29] corroborates the observations that low HSP90 expression is a positive prognostic feature. In our study we pinpointed the predictive aspect of the association of HSP90 with proliferation markers and its association with the higher response to chemotherapy.…”

Gedunin Inactivates the Co-chaperone p23 Protein Causing Cancer Cell Death by Apoptosis

“…Indeed, expression of p23 correlates with breast tumor grades, and it is highly overexpressed in malignant metastatic tissues. Importantly, microarray analysis using breast cancer cell line MCF7 showed that overexpression of p23 changes the expression levels of several genes involved in metastasis and drug resistance (29), and p23 is required for optimal cell mobility and invasion (36). Recent global analysis of p23 functions by Echtenkamp et al (47) suggests an extensive cellular network through which p23 modulates a wide range of physiological functions in a manner dependent and independent of Hsp90.…”

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

“…[1][2][3] Overexpression of these stress response proteins is observed in various cancers and linked, in some cases, to poor prognosis and resistance to chemotherapeutic treatment. 42,43 As the mitochondrial ATP-dependent Lon protease plays a similar role, assisting cells to survive and adapt to various proteotoxic stresses that are linked to oncogenesis (eg, hypoxic, oxidative, and ER stress), 10,11,15 we speculated that Lon might also be a potential anticancer drug target. For personal use only.…”