Research Report
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World J Clin Oncol. May 10, 2014; 5(2): 156-163
Published online May 10, 2014. doi: 10.5306/wjco.v5.i2.156
mRNA expression of DOK1-6 in human breast cancer
Tamara Ghanem, James Bracken, Abdul Kasem, Wen G Jiang, Kefah Mokbel
Tamara Ghanem, James Bracken, Abdul Kasem, Kefah Mokbel, London Breast Institute, Princess Grace Hospital, London, W1U 5NY, United Kingdom
Wen G Jiang, Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University, Cardiff, CF14 4XN, United Kingdom
Author contributions: All the authors contributed to this paper equally.
Correspondence to: Kefah Mokbel, Professor, London Breast Institute, Princess Grace Hospital, 42-52 Nottingham Pl, London, W1U 5NY, United Kingdom. kefahmokbel@hotmail.com
Telephone: +44-20-74861234 Fax: +44-20-79082492
Received: November 9, 2013
Revised: January 8, 2014
Accepted: January 17, 2014
Published online: May 10, 2014
Processing time: 184 Days and 10 Hours
Abstract

AIM: To examine the expression of downstream of tyrosine kinase (DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinico-pathological and prognostic factors.

METHODS: DOK1-6 mRNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples (n = 112) and normal background breast tissue (n = 31). Tissues were collected between 1991 and 1996 at two centres and all patients underwent mastectomy and ipsilateral axillary node dissection. All tissues were randomly numbered and the details were only made known after all analyses were completed. Transcript levels of expression were determined using real-time polymerase chain reaction and analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period.

RESULTS: DOK-2 and DOK-6 expression decreased with increasing TNM stage. DOK-6 expression decreased with increasing Nottingham Prognostic Index (NPI) [NPI-1 vs NPI-3 (mean copy number 15.4 vs 0.22, 95%CI: 2.7-27.6, P = 0.018) and NPI-2 vs NPI-3 (mean copy number 7.6 vs 0.22, 95%CI: 0.1-14.6, P = 0.048)]. After a median follow up period of 10 years, higher levels of DOK-2 expression were found among patients who remained disease-free compared to those who developed local or distant recurrence (mean copy number 3.94 vs 0.0000096, 95%CI: 1.0-6.85, P = 0.0091), and distant recurrence (mean copy number 3.94 vs 0.0025, 95%CI: 1.0-6.84, P = 0.0092). Patients who remained disease-free had higher levels of DOK-6 expression compared to those who died from breast cancer.

CONCLUSION: Decreasing expression levels of DOK-2 and DOK-6 with increased breast tumour progression supports the notion that DOK-2 and DOK-6 behave as tumour suppressors in human breast cancer.

Keywords: Adaptor protein; Breast cancer; Downstream of tyrosine kinase-2; Downstream of tyrosine kinase-6; Mitogen-activated protein kinase; Tyrosine kinase, Tumour suppressor

Core tip: Several members of the downstream of tyrosine kinase (DOK) protein family are identified as modulators of cell proliferation/growth pathways. In addition deregulation of specific DOK members has been associated with specific cancers. This study identifies DOK-2 and DOK-6 as potential tumor suppressors in breast cancer.