Zambrano Joelle N, Neely Benjamin A, Yeh Elizabeth S
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina Charleston, SC, USA.
Marine Biochemical Sciences, National Institute of Standards and Technology, Charleston, SC, USA.
Pharmacol Res. 2017 May;119:188-194. doi: 10.1016/j.phrs.2017.02.007. Epub 2017 Feb 9.
Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2/ErbB2) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2/ErbB2 breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2/ErbB2 breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase's role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.
激素上调的神经相关激酶（Hunk）是一种蛋白激酶，最初在小鼠乳腺中被鉴定出来，已证明在人表皮生长因子受体2阳性（HER2/ErbB2）乳腺癌细胞系以及MMTV-neu衍生的乳腺肿瘤细胞系中高表达。然而，自其被鉴定以来，Hunk的生理作用在很大程度上仍不清楚。尽管Hunk被预测为一种与蛋白激酶SNF1/AMPK家族具有同源性的丝氨酸/苏氨酸（Ser/Thr）蛋白激酶，但迄今为止尚未鉴定出已知的Hunk底物。最近的研究表明，Hunk在HER2/ErbB2乳腺癌进展中发挥作用，包括对HER2/ErbB2抑制剂的耐药性，Hunk可能在HER2/ErbB2和PI3K/Akt途径的下游起作用。这些研究共同表明，Hunk在促进乳腺肿瘤发生中起着至关重要的作用，因为在异种移植肿瘤模型中通过短发夹RNA敲低Hunk，或将MMTV-neu或Pten缺陷的基因工程小鼠模型与Hunk基因敲除（Hunk-/-）背景杂交，会损害体内乳腺肿瘤的生长。由于大多数HER2/ErbB2乳腺癌患者会对HER2/ErbB2抑制剂产生耐药性，因此鉴定像Hunk这样有可能同时抑制肿瘤发生并潜在提高当前治疗药物疗效的新型药物靶点，是药物开发的一个重要方面。因此，旨在揭示Hunk的特定调节功能，这些功能可能有助于这种蛋白激酶在肿瘤发生和耐药性中的作用的研究将具有重要意义。本综述重点关注目前对这种研究不足的蛋白激酶的了解，以及靶向Hunk如何可能被证明是治疗乳腺癌的潜在治疗靶点。
