PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorage-independent growth of MCF-7 cells in the absence of 17β-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.
This is a preview of subscription content, log in to check access.
This work was supported in part by grant RSG-116608 from the American Cancer Society and grant HL072889 from the National Institutes of Health, as well as funds from the Louisiana Cancer Research Consortium (New Orleans, LA, USA) to AH Boulares.
Miyoshi Y, Murase K, Saito M, Oh K. (2010) Prediction of hormone sensitivity for breast cancers. Breast Cancer. 17:86–91.CrossRefGoogle Scholar
Sasano H, Nagasaki S, Miki Y, Suzuki T. (2009) New developments in intracrinology of human breast cancer: estrogen sulfatase and sulfotrans-ferase. Ann. N. Y. Acad. Sci. 1155:76–9.CrossRefPubMedGoogle Scholar
Wang T, You Q, Huang FS, Xiang H. (2009) Recent advances in selective estrogen receptor modulators for breast cancer. Mini Rev. Med. Chem. 9:1191–201.CrossRefPubMedGoogle Scholar
Eroles P, Bosch A, Perez-Fidalgo JA, Lluch A. (2012) Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat. Rev. 38:698–707.CrossRefPubMedGoogle Scholar
de la Vega M, Diaz-Canton E, Alvarez RH. (2012) Novel targeted agents for the treatment of advanced breast cancer. Future Med. Chem. 4:893–914.CrossRefPubMedGoogle Scholar
Hong DS, et al. (2013) Targeting the molecular chaperone heat shock protein 90 (HSP90): lessons learned and future directions. Cancer Treat. Rev. 39:375–87.CrossRefPubMedGoogle Scholar
Garcia-Carbonero R, Carnero A, Paz-Ares L. (2013) Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol. 14:e358–69.CrossRefPubMedGoogle Scholar
Karnitz LM, Felts SJ. (2007) Cdc37 regulation of the kinome: when to hold ‘em and when to fold ‘em. Sci. STKE. 2007:pe22.CrossRefPubMedGoogle Scholar
Smith JR, Clarke PA, de Billy E, Workman P. (2009) Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors. Oncogene. 28:157–69.CrossRefGoogle Scholar
Yoon MK, Mitrea DM, Ou L, Kriwacki RW. (2012) Cell cycle regulation by the intrinsically disordered proteins p21 and p27. Biochem. Soc. Trans. 40:981–8.CrossRefPubMedGoogle Scholar
Kocher O, Comella N, Tognazzi K, Brown LF. (1998) Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains. Lab. Invest. 78:117–25.Google Scholar
Kocher O, et al. (2003) Targeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism. J. Biol. Chem. 278:52820–5.CrossRefGoogle Scholar
Ghosh MG, Thompson DA, Weigel RJ. (2000) PDZK1 and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer. Cancer Res. 60:6367–75.Google Scholar
Dunbier AK, et al. (2010) Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J. Clin. Oncol. 28:1161–7.CrossRefPubMedPubMedCentralGoogle Scholar
Kim H, et al. (2013) PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth. Mol. Med. 19:253–62.CrossRefPubMedPubMedCentralGoogle Scholar
Zerfaoui M, et al. (2010) Poly(ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation. J. Immunol. 185:1894–902.CrossRefPubMedPubMedCentralGoogle Scholar
Flowers JL, et al. (1986) Use of monoclonal antie-strogen receptor antibody to evaluate estrogen receptor content in fine needle aspiration breast biopsies. Ann. Surg. 203:250–4.CrossRefPubMedPubMedCentralGoogle Scholar
Freudenberg JA, et al. (2009) The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies. Exp. Mol. Pathol. 87:1–11.CrossRefPubMedPubMedCentralGoogle Scholar
Renoir JM, Marsaud V, Lazennec G. (2013) Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem. Pharmacol. 85:449–65.CrossRefPubMedGoogle Scholar
Moulder SL. (2010) Does the PI3K pathway play a role in basal breast cancer? Clin. Breast Cancer. 10 (Suppl. 3):S66–71.CrossRefPubMedGoogle Scholar
Agelaki S, et al. (2009) Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enhances gefitinib-induced tumor cell inhibition. Cancer Biol. Ther. 8:1470–7.CrossRefPubMedGoogle Scholar
Basso AD, et al. (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 277:39858–66.CrossRefPubMedGoogle Scholar
Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N. (2003) Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res. 63:2139–44.PubMedGoogle Scholar
Panaretou B, et al. (2002) Activation of the AT-Pase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell. 10:1307–18.CrossRefPubMedGoogle Scholar
Barrett T, et al. (2007) NCBI GEO: mining tens of millions of expression profiles—database and tools update. Nucleic Acids Res. 35:D760–5.CrossRefGoogle Scholar
Boersma BJ, et al. (2008) A stromal gene signature associated with inflammatory breast cancer. Int. J. Cancer. 122:1324–32.CrossRefPubMedGoogle Scholar
Iwamoto T, et al. (2011) Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer. J. Natl. Cancer Inst. 103:264–72.CrossRefPubMedGoogle Scholar
Hu S, et al. (2009) Systematic analysis of a simple adaptor protein PDZK1: ligand identification, interaction and functional prediction of complex. Cell. Physiol. Biochem. 24:231–42.CrossRefPubMedGoogle Scholar
Inoue J, et al. (2004) Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Am. J. Pathol. 165:71–81.CrossRefPubMedPubMedCentralGoogle Scholar
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.
The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.