title: The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer.
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.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Muhammad Saddiq
authors.initials: MS
authors.lastname: Zahari
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Renuse
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Dhanashree S
authors.initials: DS
authors.lastname: Kelkar
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Barbhuiya
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Rojas
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.affiliation: Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, U.S.A.
authors.forename: Pavani
authors.initials: P
authors.lastname: Malla
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, U.S.A.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, U.S.A.
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|Department of Oncology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.|Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD 21205, U.S.A.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human
keywords: TNK2; phosphorylation; triple negative breast cancer; tyrosine kinase