Dey Nandini, Williams Casey, Leyland-Jones Brain, De Pradip
Department of Molecular and Experimental Medicine, Avera Cancer Institute Sioux Falls, SD ; Department of Internal Medicine, SSOM, University of South Dakota SD.
Am J Transl Res. 2015 Apr 15;7(4):733-50. eCollection 2015.
ERBB3/HER3 is the most intriguing RTK by virtue of its ability to transduce multiple cytosolic signals for the proliferation and growth of tumor cells in spite of being a "kinase dead" receptor that binds to its true ligand, heregulin. Although other members of the HER3 family like EGFR and HER2 have long been recognized to be associated with breast tumorigenesis and studied because of their predictive and prognostic value, the significance of HER3 as an irrefutable component of HER family signalosome is a relatively new development. The recent understanding of signals originating from the oncogenic partnership of HER3 with HER2 in the context of HER2 amplification/overexpression showed the critical clinical value for the treatment of HER2+BC. The downstream signaling cascade (included but not limited to the PI3K signaling) associated with signals originating from HER2:HER3 dimers play a vital role in the tumorigenesis, drug-resistance and tumor progression of HER2+BC. The upregulation of HER3 activity provides an alternate "escape route" via which tumor cells bypass either the inhibition of the HER family RTKs or the inhibition of the downstream PI3K-AKT-mTOR signaling pathway. By understanding the signaling that provides this "escape route" for these tumor cells treated with a targeted therapy (HER2 inhibitors or inhibitors of downstream PI3K-AKT-mTOR signaling pathway), we are just beginning to appreciate the prognostic value of HER3 in breast cancer. In this review, we will discuss the relevance of HER3 signaling in the context of, (1) downstream oncogenic signals and (2) therapeutic options in HER2 amplified BC.
ERBB3/HER3是最具吸引力的受体酪氨酸激酶，尽管它是一种“激酶失活”的受体，可与真正的配体（神经调节蛋白）结合，但却能够转导多种胞质信号，促进肿瘤细胞的增殖和生长。虽然HER3家族的其他成员，如表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2），长期以来一直被认为与乳腺肿瘤发生有关，并因其预测和预后价值而受到研究，但HER3作为HER家族信号体中无可争议的组成部分，其重要性是一个相对较新的进展。最近对HER3与HER2在HER2扩增/过表达情况下的致癌伙伴关系所产生信号的理解，显示了其在治疗HER2阳性乳腺癌（HER2+BC）方面的关键临床价值。与HER2:HER3二聚体产生的信号相关的下游信号级联反应（包括但不限于PI3K信号通路）在HER2+BC的肿瘤发生、耐药性和肿瘤进展中起着至关重要的作用。HER3活性的上调提供了一条替代的“逃逸途径”，肿瘤细胞可借此绕过HER家族受体酪氨酸激酶的抑制或下游PI3K-AKT-mTOR信号通路的抑制。通过了解为接受靶向治疗（HER2抑制剂或下游PI3K-AKT-mTOR信号通路抑制剂）的这些肿瘤细胞提供这种“逃逸途径”的信号，我们才刚刚开始认识到HER3在乳腺癌中的预后价值。在这篇综述中，我们将讨论HER3信号在以下两方面的相关性：（1）下游致癌信号；（2）HER2扩增型乳腺癌的治疗选择。
