Brk Signals to ERK5 in Breast Cancer

蛋白酪氨酸激酶(PTKs)在调节正常细胞生长和分化中起着关键作用； 它们的过度表达可能通过增加对局部的敏感性而赋予乳腺癌细胞生长优势。 作用于多肽生长因子，或通过降低对凋亡信号的敏感性。膜的活性升高 受体PTKs存在于很大一部分乳腺肿瘤中。胞浆中可溶性PTK的总活性 大多数人类恶性乳腺癌的比例也高于良性或正常乳腺癌。 乳房组织。事实上，最近已经从恶性人类中克隆了几个新的非受体PTKs 在所检查的大多数乳腺癌中发现高度活跃和/或过度表达 到目前为止。因此，重要的是要将这些不太好描述的PTK的作用定义为新的 已知的信号通路的组成部分在很大比例的人类乳腺癌中也过度表达。 从人转移性乳腺中克隆了一种新的非受体蛋白酪氨酸激酶，命名为乳腺肿瘤激酶(BRK) 在人类乳腺癌和乳腺癌细胞系中过表达，但在 正常成人乳房组织。虽然BRK在功能上明显不同，但它与c-Src密切相关，并包含 一个SH3结构域和一个SH2结构域。在人乳腺癌细胞中，BRK被激活以响应 HERG/c-erb B_2激活和BRK基因敲除可阻断HERG诱导的ERK5激活 和细胞增殖。我们假设BRK赋予人类乳房生长和/或生存优势。 癌细胞通过作为erbB2/erbB3受体家族成员下游的信号组件而发挥作用 ERK5上游，一个新出现的乳腺细胞生长、存活和转化的关键调控因子 上皮细胞。在这里，我们将1)定义依赖于BRK的信号转导的特异性和活性 乳腺癌细胞ERK5激活途径2)检测BRK依赖的细胞生物学改变和 BRK过表达细胞和BRK基因沉默过程中的转化；3)检测BRK的作用 利用转基因技术增强erbB2信号在完整乳腺中的过度表达 老鼠模型。通过确定生长因子受体介导的信号转导的潜在机制 事件，我们将增加已知的与乳腺癌细胞生长有关的调节蛋白的库 和生存。对赫赛汀的耐药性在晚期乳腺癌患者中经常发生。非- 作用于erbB信号下游的受体PTK通路可能被证明是有用的靶点 化疗干预。

Protein tyrosine kinases (PTKs) play a critical role in the regulation of normal cell growth and differentiation; their overexpression may confer a growth advantage to breast cancer cells by increasing sensitivity to locally acting peptide growth factors, or by decreasing sensitivity to apoptotic signals. Elevated activity of membrane receptor PTKs occurs in a significant portion of breast tumors. Total soluble PTK activity in the cytosolic fractions of a majority of malignant human breast cancers is also higher than that from benign or normal breast tissue. Indeed, several novel non-receptor PTKs have recently been cloned from malignant human breast tissues and found to be highly active and/or overexpressed in a majority of breast cancers examined thus far. It is therefore important to define the role of these less well-characterized PTKs as novel components of known signaling pathways also overexpressed in a large proportion of human breast cancers. A novel nonreceptor PTK, termed breast tumor kinase (Brk) was cloned from a human metastatic breast tumor, and found to be overexpressed in human breast carcinomas and breast cancer cell lines, but not in normal adult breast tissue. Although clearly functionally distinct, Brk is closely related to c-Src, and contains one SH3-domain and one SH2-domain. In human breast cancer cells, Brk was activated in response to heregulin/c-erbB2 activation and Brk knock-down resulted in blockade of heregulin-induced ERK5 activation and cell proliferation. We hypothesize that Brk confers a growth and/or survival advantage to human breast cancer cells by acting as a signaling component downstream of erbB2/erbB3 receptor family members and upstream of ERK5, an emerging key regulator of cell growth, survival and transformation in mammary epithelial cells. Herein, we will 1) define the specificity and activity of a Brk-dependent signal transduction pathway to ERK5 activation in breast cancer cells 2) assay Brk-dependent alterations in cell biology and transformation in cells overexpressing Brk and during Brk gene-silencing, and 3) test the effects of Brk overexpression in the intact mammary gland in the context of heightened erbB2 signaling using transgenic mouse models. By identifying mechanisms underlying changes in growth factor receptor-mediated signaling events, we will increase the repertoire of regulatory proteins known to be involved in breast cancer cell growth and survival. Resistance to Herceptin is a frequent occurrence in patients with advanced breast cancer. Non- receptor PTK pathways acting downstream of erbB signaling may prove to be useful targets for chemotherapeutic intervention.