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.

LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression

“…ACK1 belongs to the family of non-receptor-tyrosine-kinases and functions as a driver of tumor progression 23 , 24 . It has been documented that knockdown of ACK1 suppresses the proliferation and invasion of breast cancer cells 25 . Although several miRNAs such as miR-7 have been shown to regulate the expression of ACK1, 26 we here propose a novel miRNA regulator of ACK1.…”

Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

“…The SIAH2 gene is a target of estrogen/estrogen receptor (ER)-signaling and mediates the ubiquitylation of Ack1 [46]. Triple negative breast cancer (TNBC) lacks ER and exhibits a high level of Ack1 [47], which correlates with high proliferation, migration and colony formation. It has been reported that constitutive activation of Ack1 can trigger the recruitment of PI3K-independent protein kinase B (PKB, also known as AKT) to the cell membrane and subsequently activate AKT in breast cancer [48], which may be the underlying mechanism of Ack1-induced tumor progression.…”

Research Progress of the Functional Role of ACK1 in Breast Cancer

“…But the nonreceptor tyrosine kinase ACK1 is activated in most aggressive TNBC cell lines. Wu et al found that inhibiting the ACK1 signal not only reduced the proliferation of TNBC cells but also promoted the invasiveness of tumor formation in xenograft mice [8]. This phenomenon indicates the dependence of TNBCs on ACK1 signal in proliferation and invasion ability.…”

“…Breast cancer research found that many ACK1 tyrosine kinase signaling proteins in many tumor cells are activated repeatedly [3–6]. ACK1 expression is positively correlated with the severity of the disease progression and negatively correlated with the survival rate in breast cancer patients [7, 8].…”

“…These signaling processes are dysfunctional during accelerated growth and differentiation of cells. It has been found that the overexpression of ACK1 is related to various tumors, including lung, prostate, stomach, pancreatic, breast, and ovarian cancers [8, 12–16]. Therefore, ACK1 plays a significant role in tumors, but the mechanism of activation and regulation in these tumors is not the same.…”