Oncotarget

Research Papers:

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer

Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Dhanashree S. Kelkar, Mustafa A. Bharbuiya, Pamela L. Rojas, Vered Stearns, Edward Gabrielson, Pavani Malla, Saraswati Sukumar, Nupam P. Mahajan and Akhilesh Pandey _

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Oncotarget. 2017; 8:2971-2983. https://doi.org/10.18632/oncotarget.13579

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Abstract

Xinyan Wu1,2,*, Muhammad Saddiq Zahari1,2,*, Santosh Renuse1,2,5, Dhanashree S. Kelkar1,2, Mustafa A. Barbhuiya2, Pamela L. Rojas1,2, Vered Stearns3, Edward Gabrielson3,4, Pavani Malla6, Saraswati Sukumar3, Nupam P. Mahajan6,7, Akhilesh Pandey1,2,3,4

1Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A

2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A

3Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A

4Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A

5Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India

6Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, U.S.A

7Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, U.S.A

*These authors have contributed equally to this work

Correspondence to:

Xinyan Wu, email: [email protected]

Nupam P. Mahajan, email: [email protected]

Akhilesh Pandey, email: [email protected]

Keywords: TNK2, triple negative breast cancer, tyrosine kinase, phosphorylation

Received: March 11, 2016    Accepted: October 10, 2016    Published: November 25, 2016

ABSTRACT

Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines. In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro and tumor formation in xenograft mouse models. Moreover, inhibition of TNK2 with small molecule inhibitor (R)-9bMS significantly compromised TNBC proliferation.

Finally, we find that high levels of TNK2 expression in high-grade basal-like breast cancers correlates significantly with poorer patient outcome. Taken together, our study suggests that TNK2 is a novel potential therapeutic target for the treatment of TNBC.


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