Advertisement

Molecular Medicine

, Volume 19, Issue 1, pp 253–262 | Cite as

PDZK1 Is a Novel Factor in Breast Cancer That Is Indirectly Regulated by Estrogen through IGF-1R and Promotes Estrogen-Mediated Growth

  • Hogyoung Kim
  • Zakaria Y Abd Elmageed
  • Jihang Ju
  • Amarjit S Nauru
  • Asim B Abdel-Mageed
  • Shibu Varughese
  • Dennis Paul
  • Suresh Alahari
  • Andrew Catling
  • Jong G Kim
  • A Hamid Boulares
Research Article

Abstract

Although a relationship between PDZK1 expression and estrogen receptor (ER)-α stimulation has been suggested, the nature of such a connection and the function of PDZK1 in breast cancer remain unknown. Human tissue microarrays (cancer tissue: 262 cores; normal tissue: 87 cores) and breast cancer cell lines were used to conduct the study. We show that PDZK1 protein expression is tightly correlated with human breast malignancy, is negatively correlated with age and had no significant correlation with ER-α expression levels. PDZK1 exhibited an exclusive epithelial expression with mostly cytosolic subcellular localization. Additionally, 17β-estradiol induced PDZK1 expression above its basal level more than 24 h after treatment in MCF-7 cells. PDZK1 expression was indirectly regulated by ER-α stimulation, requiring insulinlike growth factor 1 receptor (IGF-1R) expression and function. The molecular link between PDZK1 and IGF-1R was supported by a significant correlation between protein and mRNA levels (r = 0.591, p < 0.001, and r = 0.537, p < 0.001, respectively) of the two factors in two different cohorts of human breast cancer tissues. Interestingly, PDZK1 knockdown in MCF-7 cells blocked ER-dependent growth and reduced c-Myc expression, whereas ectopic expression of PDZK1 enhanced cell proliferation in the presence or absence of 17β-estradiol potentially through an increase in c-Myc expression, suggesting that PDZK1 has oncogenic activity. PDKZ1 also appeared to interact with the Src/ER-α/epidermal growth factor receptor (EGFR) complex, but not with IGF-1R and enhanced EGFR-stimulated MEK/ERK1/2 signaling. Collectively, our results clarify the relationship between ER-α and PDZK1, propose a direct relationship between PDZK1 and IGF-1R, and identify a novel oncogenic activity for PDZK1 in breast cancer.

Notes

Acknowledgments

This work was supported in part by grant RSG-116608 from the American Cancer Society and grant HL072889 from the National Institutes of Health (NIH) as well as funds from the Louisiana Cancer Research Consortium (New Orleans, LA, USA) to AH Boulares. This work was also supported in part by grant P20GM103501 (NIH/COBRE) to AS Naura (overall principal investigator: A Ochoa) and by grant PJ008047 from the Next-Generation BioGreen 21 Program Rural Development Administration (Republic of Korea) to JG Kim.

Supplementary material

10020_2013_1901253_MOESM1_ESM.pdf (1.5 mb)
Supplementary material, approximately 1.52 MB.

References

  1. 1.
    Bai Z, Gust R. (2009) Breast cancer, estrogen receptor and ligands. Arch. Pharm. (Weinheim). 342:133–49.CrossRefGoogle Scholar
  2. 2.
    Fox EM, Andrade J, Shupnik MA. (2009) Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. Steroids. 74:622–7.CrossRefPubMedGoogle Scholar
  3. 3.
    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.PubMedGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    Kocher O, Krieger M. (2009) Role of the adaptor protein PDZK1 in controlling the HDL receptor SR-BI. Curr. Opin. Lipidol. 20:236–41.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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.PubMedGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Raff T, van der Giet M, Endemann D, Wiederholt T, Paul M. (1997) Design and testing of beta-actin primers for RT-PCR that do not co-amplify processed pseudogenes. Biotechniques. 23:456–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Oumouna-Benachour K, et al. (2007) Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 115:2442–50.CrossRefPubMedGoogle Scholar
  11. 11.
    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
  12. 12.
    Song RX, Zhang Z, Chen Y, Bao Y, Santen RJ. (2007) Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells. Endocrinology. 148:4091–101.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ptak A, Gut P, Blachuta M, Rak A, Gregoraszczuk EL. (2009) Direct inhibition of ERK1/2 phosphorylation as a possible mechanism for the antiproliferative action of 3,4-diOH-PCB3 in the MCF-7 cell line. Toxicol. Lett. 190:187–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Barrett T, et al. (2007) NCBI GEO: mining tens of millions of expression profiles: database and tools update. Nucleic Acids Res. 35:D760–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Boersma BJ, et al. (2008) A stromal gene signature associated with inflammatory breast cancer. Int. J. Cancer. 122:1324–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Saddar S, Mineo C, Shaul PW. (2010) Signaling by the high-affinity HDL receptor scavenger receptor B type I. Arterioscler. Thromb. Vasc. Biol. 30:144–50.CrossRefPubMedGoogle Scholar
  17. 17.
    Spears M, Bartlett J. (2009) The potential role of estrogen receptors and the SRC family as targets for the treatment of breast cancer. Expert Opin. Ther. Targets. 13:665–74.CrossRefPubMedGoogle Scholar
  18. 18.
    Santen RJ, et al. (2009) Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids. 74:586–94.CrossRefPubMedGoogle Scholar
  19. 19.
    Rajhans R, et al. (2008) Modulation of in situ estrogen synthesis by proline-, glutamic acid-, and leucine-rich protein-1: potential estrogen receptor autocrine signaling loop in breast cancer cells. Mol. Endocrinol. 22:649–64.CrossRefPubMedGoogle Scholar
  20. 20.
    Miyoshi Y, Murase K, Saito M, Oh K. (2010) Prediction of hormone sensitivity for breast cancers. Breast Cancer. 17:86–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Miller WR, O’Neill J. (1987) The importance of local synthesis of estrogen within the breast. Steroids. 50:537–48.CrossRefPubMedGoogle Scholar
  22. 22.
    Frasor J, et al. (2004) Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res. 64:1522–33.CrossRefPubMedGoogle Scholar
  23. 23.
    Mackay A, et al. (2007) Molecular response to aromatase inhibitor treatment in primary breast cancer. Breast Cancer Res. 9:R37.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Englert NA, Spink BC, Spink DC. (2011) Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J. Steroid. Biochem. Mol. Biol. 123:140–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Saceda M, et al. (1988) Regulation of the estrogen receptor in MCF-7 cells by estradiol. Mol. Endocrimol. 2:1157–62.CrossRefGoogle Scholar
  26. 26.
    Shupnik MA. (2004) Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene. 23:7979–89.CrossRefPubMedGoogle Scholar
  27. 27.
    Lefevre G, et al. (2003) Opposite long-term regulation of c-Myc and p27Kip1 through overactivation of Raf-1 and the MEK/ERK module in proliferating human choroidal melanoma cells. Oncogene. 22:8813–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhu W, et al. (2008) The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity. Circ. Res. 102:480–7.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2013

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.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Hogyoung Kim
    • 1
  • Zakaria Y Abd Elmageed
    • 2
  • Jihang Ju
    • 1
  • Amarjit S Nauru
    • 1
    • 3
  • Asim B Abdel-Mageed
    • 2
  • Shibu Varughese
    • 3
  • Dennis Paul
    • 1
  • Suresh Alahari
    • 1
  • Andrew Catling
    • 1
  • Jong G Kim
    • 1
  • A Hamid Boulares
    • 1
  1. 1.The Stanley Scott Cancer CenterLouisiana State University Health Sciences CenterNew OrleansUSA
  2. 2.Department of UrologyTulane Medical CenterNew OrleansUSA
  3. 3.Department of MedicineLouisiana State University Health Sciences CenterNew OrleansUSA

Personalised recommendations