Regulation of PTK6 expression and oncogenic function in breast tumor progression

 描述（由申请人提供）：三阴性乳腺癌（TNBC）相对于其他乳腺癌亚型具有更差的预后和结局。因此，必须鉴定新的分子和途径以用于TNBC患者的靶向治疗。蛋白酪氨酸激酶6（PTK 6）是一种可溶性酪氨酸激酶，在86%的乳腺癌中异常表达，在正常乳腺上皮细胞中不存在。乳腺肿瘤中PTK 6的高表达与转移增加和总生存期缩短相关。这些数据表明PTK 6在乳腺癌进展中的肿瘤特异性作用，并使PTK 6和PTK 6诱导的信号通路成为乳腺癌治疗的有吸引力的靶点。PTK 6在多种生长因子受体的下游被激活，包括Her 2/neu、EGFR和MET受体。在乳腺上皮细胞中表达的背景下，PTK 6作为高表达生长因子受体下游的致癌“节点”，并发挥传播致癌信号传导事件的功能，导致迁移能力增强。PTK 6在乳腺癌细胞中获得表达的机制在很大程度上是未知的，并且仍然不清楚PTK 6如何与细胞内信号通路整合。我们的目标是确定TNBC中PTK 6异常表达的机制，并了解PTK 6在侵袭性基底型乳腺肿瘤的肿瘤发生和进展中的功能。为了解决这些问题，本提案将重点关注理解负责诱导PTK 6表达的因子之间的串扰，包括缺氧诱导因子（HIF）转录因子和应激类固醇激素受体，糖皮质激素受体（GR）。我们的初步数据表明，HIF和GR协同诱导TNBC中的PTK 6表达，最终使癌细胞适应生理细胞应激和应激激素信号传导。此外，我们将通过转基因小鼠模型确定小鼠PTK 6（Sik）在驱动基底型乳腺肿瘤发生中的作用，其中Sik敲除（KO）小鼠与具有组成型活性MET受体信号传导的METmut小鼠杂交。所得到的Sik-KO/METmut小鼠将允许我们评估当Sik不存在时肿瘤数量、潜伏期、等级和转移的变化。这些研究将为乳腺癌中PTK 6表达的调节以及PTK 6信号传导作为生长因子受体下游TNBC中致癌驱动因子的后续功能提供新的见解。

 DESCRIPTION (provided by applicant): Triple-negative breast cancers (TNBC) have a worse prognosis and outcome relative to other breast cancer subtypes. As such, it is imperative that new molecules and pathways be identified to exploit for targeted therapy in patients with TNBC. Protein tyrosine kinase 6 (PTK6) is a soluble tyrosine kinase that is aberrantly expressed in 86% of breast cancers and absent from normal mammary epithelial cells. High expression of PTK6 in breast tumors is associated with increased metastasis and shortened overall survival. These data suggest a tumor specific role for PTK6 in breast cancer progression and make PTK6 and PTK6-induced signaling pathways attractive targets for breast cancer treatment. PTK6 is activated downstream of a diverse group of growth factor receptors, including Her2/neu, EGFR, and MET receptors. In this context of expression in mammary epithelial cells, PTK6 acts as an oncogenic "node" downstream of highly expressed growth factor receptors, and functions to propagate oncogenic signaling events resulting in enhanced migratory ability. Mechanisms through which PTK6 expression is acquired in breast cancer cells are largely unknown and it is still unclear how PTK6 integrates with intracellular signaling pathways. Our goal is to define the mechanisms of aberrant PTK6 expression in TNBC and to understand the function of PTK6 in the tumorigenesis and progression of aggressive, basal-type mammary tumors. To address these questions, this proposal will focus on understanding the cross-talk between factors responsible for induction of PTK6 expression, including the hypoxia-inducible factor (HIF) transcription factors and the stress steroid hormone receptor, the glucocorticoid receptor (GR). Our preliminary data suggest that HIFs and GR cooperate to induce PTK6 expression in TNBC, to ultimately allow the cancer cells to adapt to both physiologic cell stress and stress hormone signaling. Moreover, we will determine the role of mouse PTK6 (Sik) in driving basal-type mammary tumorigenesis via a transgenic mouse model in which Sik knockout (KO) mice are crossed to METmut mice with constitutively active MET receptor signaling. The resulting Sik-KO/METmut mice will allow us to assess changes in tumor number, latency, grade and metastasis when Sik is not present. These studies will provide novel insight in the regulation of PTK6 expression in breast cancer and the subsequent function of PTK6 signaling as an oncogenic driver in TNBC downstream of growth factor receptors.