Skip to main content


Log in

Down-regulation of PHLDA1 gene expression is associated with breast cancer progression

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript


In a previous study, using differential display reverse transcriptase-PCR (DDRT-PCR) we showed that down-regulation of the PHLDA1 (pleckstrin homology-like domain, family A, member 1; also named TDAG51) mRNA was down-regulated in breast tumors compared with normal breast tissue. The present study was conducted to determine the expression pattern and predictive prognostic value of PHLDA1 in breast cancer. A series of 720 primary invasive breast tumors were examined for PHLDA1 expression. PHLDA1 mRNA expression was determined in 74 breast tumors using quantitative Real Time PCR analysis (qPCR). PHLDA1 protein expression was evaluated by immunohistochemistry (IHC) using Tissue Microarrays (TMA) containing 699 primary invasive breast tumors. Reduced PHLDA1 mRNA expression was identified in 72% (53/74) of the primary breast tumors analyzed. Seventy-three percent (512/699) of cases analyzed showed negative PHLDA1 protein expression. Down-regulation of PHLDA1 protein was a strong predictor of poor prognosis for breast cancer patients. Breast cancer patients with tumors that were negative for PHLDA1 protein expression had shorter disease free survival (P < 0.001) and overall survival (P < 0.001) than patients with tumors that were positive for PHLDA1 protein expression. In addition patients with tumors exhibiting reduced PHLDA1 expression and paucity for ER had the worse outcome (P < 0.001). Multivariate analysis indicated that PHLDA1 protein expression is an independent prognostic factor of patient survival. To our knowledge, the expression pattern of PHLDA1 in breast cancer has not previously been investigated. Our results provide strong evidence that reduced PHLDA1 expression is important in breast cancer progression and could serve as useful prognostic marker of disease outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others


  1. Boyle P (2005) Breast cancer control: signs of progress, but more work required. Breast 14(6):429–438

    Article  PubMed  Google Scholar 

  2. Van ‘t Veer LJ, Dai H, et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  PubMed  Google Scholar 

  3. Rouzier R, Perou CM, Symmans WF et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 15:11(16):5678–5685

    Google Scholar 

  4. Folgueira MA, Carraro DM, Brentani H et al (2005) Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res 11(20):7434–7443

    Article  PubMed  CAS  Google Scholar 

  5. Duffy MJ (2005) Predictive markers in breast and other cancers: a review. Clin Chem 51(3):494–503

    Article  PubMed  CAS  Google Scholar 

  6. Nagai MA, Ros N, Bessa SA et al (2003) Differentially expressed genes and estrogen receptor status in breast cancer. Int J Oncol 23(5):1425–1430

    PubMed  CAS  Google Scholar 

  7. Park CG, Lee SY, Kandala G et al (1996) A novel gene product that couples TCR signaling to Fas(CD95) expression in activation-induced cell death. Immunity 4(6):583–591

    Article  PubMed  CAS  Google Scholar 

  8. Kuske MD, Johnson JP (2000) Assignment of the human PHLDA1 gene to chromosome 12q15 by radiation hybrid mapping. Cytogenet Cell Genet 89(1–2):1

    Article  PubMed  CAS  Google Scholar 

  9. Gomes I, Xiong W, Miki T et al (1999) A proline- and glutamine-rich protein promotes apoptosis in neuronal cells. J Neurochem 73(2):612–622

    Article  PubMed  CAS  Google Scholar 

  10. Hossain GS, van Thienen JV, Werstuck GH et al (2003) TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocysteinemia. J Biol Chem 278(32):30317–30327

    Article  PubMed  CAS  Google Scholar 

  11. Toyoshima Y, Karas M, Yakar S et al (2004) TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival. J Biol Chem 279(24):25898–25904

    Article  PubMed  CAS  Google Scholar 

  12. Brentani MM, Nagai MA, Fujyama CT et al (1981) Steroid receptors in a group of Brazilian breast cancer patients. J Surg Oncology 18:431–439

    Article  CAS  Google Scholar 

  13. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  14. Neef R, Kuske MA, Prols E et al (2002) Identification of the human PHLDA1/TDAG51 gene: down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation. Cancer Res 62(20):5920–5929

    PubMed  CAS  Google Scholar 

  15. Hardy K, Mansfield L, Mackay A et al (2005) Transcriptional networks and cellular senescence in human mammary fibroblasts. Mol Biol Cell 16(2):943–953

    Article  PubMed  CAS  Google Scholar 

  16. Green KA, Streuli CH (2004) Apoptosis regulation in the mammary gland. Cell Mol Life Sci 61(15):1867–1883

    Article  PubMed  CAS  Google Scholar 

  17. Fata JE, Werb Z, Bissell MJ (2004) Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res 6(1):1–11

    PubMed  CAS  Google Scholar 

  18. Rho J, Gong S, Kim N et al (2001) TDAG51 is not essential for Fas/CD95 regulation and apoptosis in vivo. Mol Cell Biol 21(24):8365–8370

    Article  PubMed  CAS  Google Scholar 

Download references


This work was supported by grants 03/13170–0 and 04/04607–8 from FAPESP.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Maria Aparecida Nagai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagai, M.A., Fregnani, J.H.T.G., Netto, M.M. et al. Down-regulation of PHLDA1 gene expression is associated with breast cancer progression. Breast Cancer Res Treat 106, 49–56 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: