Brk Signals to ERK5 in Breast Cancer

蛋白酪氨酸激酶（PTKs）在正常细胞生长和分化的调节中起关键作用; 它们的过度表达可能通过增加局部对肿瘤的敏感性而赋予乳腺癌细胞生长优势。 作用肽生长因子，或通过降低对凋亡信号的敏感性。膜活性升高 受体PTK存在于大部分乳腺肿瘤中。胞质中总可溶性PTK活性 大多数恶性人类乳腺癌的分数也高于良性或正常乳腺癌 乳房组织事实上，最近已经从恶性肿瘤患者中克隆了几种新的非受体PTKs， 乳腺组织中，并发现在大多数检查的乳腺癌中高度活跃和/或过表达 到目前为止。因此，重要的是将这些特征不太明确的PTK的作用定义为新的 已知信号通路的组分也在大部分人乳腺癌中过表达。 从人转移性乳腺癌组织中克隆了一种新的非受体PTK，称为乳腺肿瘤激酶（Brk 在人乳腺癌和乳腺癌细胞系中过表达，但在人乳腺癌和乳腺癌细胞系中不表达。 正常成人乳房组织尽管在功能上明显不同，但Brk与c-Src密切相关，并且包含 一个SH 3结构域和一个SH 2结构域。在人乳腺癌细胞中，Brk被激活， heregulin/c-erbB 2激活和Brk敲低导致heregulin诱导的ERK 5激活的阻断 和细胞增殖。我们假设Brk赋予人类乳腺癌生长和/或存活优势 通过作为erbB 2/erbB 3受体家族成员下游的信号传导组分作用于癌细胞， ERK 5上游，一种新出现的乳腺癌细胞生长、存活和转化的关键调节因子 上皮细胞在此，我们将1）定义Brk依赖性信号转导的特异性和活性， 2）测定细胞生物学中的Brk依赖性改变， 在过表达Brk的细胞中和在Brk基因沉默期间的转化，和3）测试Brk的作用 使用转基因技术在增强erbB 2信号传导的情况下在完整乳腺中的过度表达 小鼠模型。通过确定生长因子受体介导的信号转导的潜在变化机制， 事件，我们将增加已知参与乳腺癌细胞生长的调节蛋白的库 和生存。对赫赛汀的耐药在晚期乳腺癌患者中经常发生。非 作用于erbB信号传导下游的受体PTK途径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.