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High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas

Authors Khan Z, Arafah M, Shaik JP, Mahale A, Alanazi MS

Received 18 October 2017

Accepted for publication 4 December 2017

Published 11 January 2018 Volume 2018:11 Pages 323—335

DOI https://doi.org/10.2147/OTT.S154395

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr William Cho


Zahid Khan,1 Maha Arafah,2 Jilani Purusottapatnam Shaik,1 Alka Mahale,3 Mohammad Saud Alanazi1

1Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, 2Department of Pathology, College of Medicine, King Saud University, Riyadh, 3King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia

Purpose: Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients.
Materials and methods: We immunohistochemically examined various components of Wnt signaling pathway including β-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women.
Results: Cytoplasmic β-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of β-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic β-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers.
Conclusions: High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs targeting this pathway.

Keywords:
breast cancer, Wnt signaling pathway, immunohistochemistry, β-catenin
 

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