Amphiregulin Signaling in Human Breast Cancer

我们已经发现，大约一半的基底类型乳腺癌表现出 双调节蛋白(AREG)自分泌激活EGFR。此外，我们的数据表明，当 AREG是EGFR的激活配体，受体运输和下游信号传递是戏剧性的 改变导致建立一个涉及核因子-B和白介素1的正反馈回路， 表达一个独特的转录模式，并获得运动和侵袭能力。这个 本申请中提出的工作的总体目标是阐明AREG如何从根本上 改变人类乳腺癌细胞的生物学，并有助于表型的表达 具有侵袭性的人类乳腺癌的特征，并检验AREG的作用是 通过激活核因子-B和白介素1进行调节。该项目的具体目标是：1)测试 假设EGFR在细胞表面的积累，发生在AREG刺激的细胞和 而不是EGF刺激的细胞，是导致EGFR信号改变的最接近的机制 核因子-B的激活和IL-1的表达，2)确定EGFR信号体的组成 在AREG刺激的细胞中，阐明AREG激活的EGFR到核的信号通路 核因子-B的积累，并分析这一途径在侵袭性生长表达中的作用 乳腺癌细胞的表型，3)确定IL-1信号如何调节EGFR酪氨酸 AREG/EGFR自分泌对乳腺癌细胞和乳腺上皮细胞的磷酸化作用 环路通过影响靶向EGFR的酪氨酸磷酸酶和/或酪氨酸激酶的活性，以及 4)确定在具有AREG/EGFR自分泌环路的乳腺癌中，EGFR抑制是否导致- IL-1的调节和核转录因子-kB的核丢失。AREG激活EGFR从根本上改变了 高侵袭性和耐药乳腺HME细胞的生物学及诱导表型 癌细胞。理解这种差异的机制基础，并理解 AREG介导的EGFR激活的下游后果将提高我们的理解 一种特别侵袭性的乳腺癌的生物学亚类，目前还没有治疗方法 除了标准化疗之外的其他选择。

We have found that approximately half of basal type breast cancers show evidence for autocrine activation of the EGFR by amphiregulin (AREG). Furthermore, our data indicate that when AREG is the activating ligand for EGFR, receptor trafficking and down stream signaling is dramatically altered resulting in the establishment of a positive feedback loop involving NF-B and IL-1, the expression of a distinctive transcription profile, and the acquisition of motile and invasive capacity. The over arching goal of the work proposed in this application is to elucidate how AREG fundamentally alters the biology of human breast cancer cells and contributes to the expression of phenotypes characteristic of aggressive human breast cancer, and to test the hypothesis that AREG's effects are mediated via activation of NF-B and IL-1. The specific aims of this project are: 1) To test the hypothesis that accumulation of EGFR at the cell surface, which occurs in AREG stimulated cells and not EGF-stimulated cells, is the proximate mechanism for the altered EGFR signaling that results in activation of NF-B and expression of IL-1, 2) To determine the components of the EGFR signalosome in AREG stimulated cells, to elucidate the signaling pathway from AREG-activated EGFR to the nuclear accumulation of NF-B, and to analyze the role of this pathway in the expression of aggressive growth phenotypes of basal breast cancer cells, 3) To determine how IL-1 signaling modulates EGFR tyrosine phosphorylation in breast cancer cells and mammary epithelial cells with an AREG/EGFR autocrine loop by influencing the activity of tyrosine phosphatases and/or tyrosine kinases that target EGFR, and 4) to determine if EGFR-inhibition in breast cancers with AREG/EGFR autocrine loops results in down- regulation of IL-1, and loss of nuclear of NF-kB. AREG activation of EGFR fundamentally alters the biology of HME cells and induces phenotypes expressed by highly aggressive and drug-resistant breast cancer cells. Understanding the mechanistic basis for this difference, and understanding the downstream consequences of AREG mediated activation of the EGFR will improve our understanding of the biology of a particularly aggressive subclass of breast cancer for which there are no therapeutic options beyond standard chemotherapy.