HEREGULIN AND BREAST CANCER PROGRESSION

描述：(改编自调查人员的摘要) 乳腺癌是美国最常见的恶性肿瘤之一。 每九个州中就有一名妇女受到影响。生长因子及其受体 对调节上皮细胞的增殖起着至关重要的作用。 它们在表达和动作上的异常导致了 恶性表型的进展和维持。例如： C-erbB-2/HER2基因产物的过度表达是常见的 与积极的临床病程相关，减少无病 人类乳腺癌的存活率和转移增加。同样， Hereglin结合区对HER2受体的反式激活作用 (HRG)对其受体(HER3或HER4)的作用促进 激素非依赖性和更具攻击性的表型。这件事的重点是 建议建立HRG的分子机制(S)。 参与乳房更具侵袭性的表型的发展 癌细胞。这项建议背后的理由是基于最近的 人乳腺癌细胞HRG刺激导致的观察(I) 与F-肌动蛋白的诱导有关(II)E-肌动蛋白与E-肌动蛋白之间的结合减弱 细胞-细胞界面的钙粘附素和β-连环素，(Iii)增加 β-连环蛋白和小GTP酶cdc42之间的物理联系， (Iv)p21激活的激酶(PAK)的激活和重分布 前缘和(V)片脂/丝足的发育。在……里面 此外，这些分子变化伴随着一种刺激 乳腺癌细胞通过多孔膜的迁移和 细胞外分泌的生物活性金属蛋白酶-9增加。这些 研究表明：(I)控制细胞的细胞骨架复合体 细胞黏附和细胞运动可能在细胞中起着重要作用 HRG在乳腺癌细胞中的迁移和侵袭功能及(II) 在HRG信号和控制信号的通路之间发生串扰 乳腺癌细胞的迁移和黏附表型； 从而可能导致侵袭力增强。他们的中心假设是 高密度脂蛋白信号通路的激活(S)可能会影响功能。 和/或表达调节细胞黏附的特定基因产物， 应力纤维的形成、膜的褶皱和细胞的迁移， 因此，可能有助于细胞迁移的发展。 乳腺癌细胞的侵袭性表型。 建议(1)建立HRG的细胞迁移功能(Aim1)。 (2)建立HRG作用和调制之间的功能联系 细胞骨架复合体和细胞间的相互作用，以及 确定调控发育的信号转导途径 板脂/丝足和细胞迁移(目标2和3)。(3)至 建立信号通路，这可能是负责 HRG诱导的乳腺癌细胞(Aim4)中基质金属蛋白酶-9表达上调。其中之一 我们提案的独特/创新之处在于，我们将描绘 在信令级联中，HRG生成的信号是 通过影响细胞的发育而有利于细胞的迁移 丝状/片状脂体或通过诱导基质金属蛋白酶-9的表达而向侵袭方向发展。 这项拟议研究的意义在于，它可能导致 加深对所涉及的基本分子过程的理解 在HER2/HRG中，调节细胞的迁移和侵袭功能。它还可能 为治疗药物的发展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.