HEREGULIN AND BREAST CANCER PROGRESSION

描述：（改编自研究者摘要） 乳腺癌是美国最常见的恶性肿瘤之一， 影响到九分之一的女性。生长因子及其受体 在调节上皮细胞增殖中起重要作用。 在他们的表达和行动中， 恶性表型的进展和维持。举例来说： c-erbB-2/HER 2基因产物的过表达通常 与侵袭性临床病程相关，无病 存活率和转移增加。同样地， 调蛋白结合区对HER 2受体的反式激活作用 (HRG)其受体（HER 3或HER 4）促进了 非依赖性和更具攻击性的表型。的重点 建议是建立HRG的分子机制 参与乳腺更具侵袭性表型的形成 癌细胞这一建议背后的理由是， 观察到HRG刺激人乳腺癌细胞导致（i） （ii）E-肌动蛋白与F-肌动蛋白的诱导之间的联系减少， （iii）增加细胞-细胞界面的钙粘蛋白和β-连环蛋白， β-连环蛋白和小GTdc 42之间的物理关联， (iv)p21激活激酶（PAK）的激活和重新分布， 前缘和（v）板状伪足/丝状伪足的发育。在 此外，这些分子变化伴随着刺激， 乳腺癌细胞通过多孔膜的迁移， 增加生物活性金属蛋白酶-9的细胞外分泌。这些 研究结果表明，（i）控制细胞的细胞骨架复合物， 细胞粘附和细胞运动性可能在细胞中具有重要作用 HRG在乳腺癌细胞中的迁移和侵袭功能，以及（ii） 在HRG信号传导和控制HRG信号传导的通路之间发生串扰， 乳腺癌细胞的细胞迁移和粘附表型，以及 从而可能导致入侵增强。他们的核心假设是， “HRG信号通路的激活可能会影响 和/或调节细胞粘附的特定基因产物的表达， 应力纤维形成、膜褶皱和细胞迁移， 因此，可能有助于细胞迁移的发展， 乳腺癌细胞的侵袭表型。“这项工作的总体目标是 建议（1）建立HRG（Aim 1）的细胞迁移功能。 (2)在HRG作用和调节之间建立功能联系 细胞骨架复合物和细胞与细胞相互作用， 确定调节发育的信号转导途径 板状伪足/丝状伪足和细胞迁移（目的2和3）。(3)到 建立信号通路，可能是负责 HRG处理的乳腺癌细胞中MMP-9的上调（Aim 4）。之一 我们的提案的独特/创新方面是，我们将描述 在该点处，在信令级联中， 分叉有利于细胞迁移的影响发展， 丝状伪足/板状伪足或通过诱导MMP-9表达而走向入侵。 这项研究的重要性在于，它可能会导致一个 加深对所涉及的基本分子过程的理解 在HER 2/HRG调节细胞迁移和侵袭功能中的作用。它也可以 为治疗药物的开发提供新的细胞内靶点 抑制乳腺癌进展的药物。

DESCRIPTION: (adapted from the investigator's abstract) Breast cancer is one of the most common malignancies in the United States, affecting one in nine women. Growth factors and their receptors play an essential role regulating the proliferation of epithelial cells. Abnormalities in their expression and action contribute to the progression and maintenance of the malignant phenotype. For example: overexpression of the c-erbB-2/HER2 gene product is frequently associated with an aggressive clinical course, reduced disease-free survival, and increased metastasis in human breast cancer. Similarly, transactivation of HER2 receptor by the binding region of heregulin (HRG) to its receptors (HER3 or HER4) promotes the development of the hormone-independent and more aggressive phenotype. The focus of this proposal is to establish the molecular mechanism(s) by which HRG participate in the development of the more invasive phenotype in breast cancer cells. The rationale behind this proposal is based on the recent observations that HRG-stimulation of human breast cancer cells leads (i) to the induction of F-actin (ii) a decreased association between E- cadherin and beta-catenin at the cell-cell interface, (iii) increased physical association between beta-catenin and the small GTPase cdc42, (iv) activation and a redistribition of p21 activated kinase (PAK) at the leading edge and (v) the development of lamellipodia/filapodia. In addition, these molecular changes are accompanied by a stimulation of trans-migration of breast cancer cells through a porous membrane and increased extracellular secretion of bioactive metalloprotease-9. These findings suggest that (i) cytoskeletal complexes that control cell to cell adhesion and cell motility may have a significant role in the cell migration and invasion functions of HRG in breast cancer cells and (ii) cross talk occurs between HRG signaling and the pathways that control the cell migration and adhesion phenotype of breast cancer cells, and thus may lead to enhance invasion. Their central hypothesis is that "activation of the HRG-signaling pathway(s) may influence the function and/or expression of specific gene products that regulate cell adhesion, stress fiber formation, membrane ruffling and cell migration and, therefore, may contribute to the development of the cell migration/ invasive phenotype of breast cancer cells." The overall goals of this proposal are (1) to establish the cell migration function of HRG (Aim1). (2) To establish a functional link between HRG action and the modulation of cytoskeletal complexes and cell to cell interactions, and to determine the signal transduction pathways that regulate the development of lamellipodia/filapodia and cell migration (Aims 2 and 3). (3) To establish the signaling pathways that may be responsible for the upregulation of MMP-9 in HRG treated breast cancer cells (Aim4). One of the unique/innovative aspects of our proposal is that we will delineate at which point in the signaling cascades HRG generated signals are bifurcated in favor of cell migration by influencing the development of filapodia/lamellipodia or toward invasion by inducing MMP-9 expression. The significance of the proposed research is that it may lead to an enhanced understanding of the fundamental molecular processes involved in HER2/HRG regulate cell migration and invasion functions. It may also provide new intracellular targets for the development of therapeutic agents to inhibit breast cancer progression.