Pathways that regulate basal and metastatic phenotypes in triple negative breast cancers

调节三阴性乳腺癌基础表型和转移表型的途径

• 批准号: 10059304
• 负责人: Teresa L Wood
• 金额: $ 3.39万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059304
• 关键词: Binding; Breast; Breast Cancer Cell; Breast Cancer cell line; Colorectal Neoplasms; Data; Databases; Development; Disseminated Malignant Neoplasm; Epithelial; Epithelium; Fibroblasts; Human; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Knowledge; Ligands; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mus; Neoplasm Metastasis; Pathway interactions; Phenotype; Receptor Signaling; Reporting; Research Project Grants; Signal Transduction; Testing; Therapeutic; WNT Signaling Pathway; autocrine; beta catenin; design; experimental study; insight; malignant breast neoplasm; mouse model; neoplastic cell; paracrine; parent grant; receptor; receptor expression; receptor function; triple-negative invasive breast carcinoma; tumorigenesis

The current studies are a supplement to a proposal on what regulates basal and metastatic phenoytpes in triple negative breast cancer (TNBC) with a focus on the function of the insulin-like growth factor type 1 receptor (IGF-1R). The proposed supplementary research project will extend studies related to Aim 1 of the parent grant that were designed to investigate the interaction between the IGF-1R and the Wnt signaling pathway. Our recent analysis of the human breast cancer database revealed an inverse correlation Wnt2 and its receptor, Frizzled 9 (Fzd9), and IGF-1R expression. Moreover, in Wnt-driven mouse mammary tumors with reduced IGF-1R signaling leading to a metastatic phenotype, we also identified increased Wnt2 and Fzd9 expression. Wnt2 is the prominent Wnt ligand for Fzd9, and this signaling loop follows the canonical Wnt pathway wherein Wnt2 binding to Fzd9 increases the levels of total β-catenin. Expression of Wnt2 and Fzd9 are elevated in several different kinds of cancer including breast, and Wnt2 promotes the development of a more invasive, metastatic cancer phenotype in breast and colorectal tumor cells. Our preliminary data further confirm that Fzd9 is upregulated in the human luminal epithelial MCF7 breast cancer cell line after inhibiting IGF-1R. Wnt2 expression has been reported in cancer-associated fibroblasts (CAFs); our preliminary data show that some human breast cancer cells also express Wnt2 in addition to Fzd9 suggesting this signaling loop can act in both a paracrine and autocrine manner. Taken together, the data provide the basis for our new hypothesis that reduced levels of IGF-1R in breast cancer leads to increased activation of the Wnt2/Fzd9 signaling loop. This will be tested by the following two specific aims: 1) Determine how the Wnt2/Fzd9 signaling axis is regulated by reduced IGF-1R signaling and define the cellular components responsible for Wnt2 expression. 2) Investigate how the Wnt2/Fzd9 signaling axis alters tumor cell phenotype in the context of reduced IGF-1R function.

目前的研究是对关于什么调节基础和 三阴性乳腺癌（TNBC）的转移表型，重点关注 胰岛素样生长因子1型受体（IGF-1 R）。拟议的补充研究 该项目将扩展与父母补助金目标1相关的研究，这些研究旨在调查 IGF-1 R和Wnt信号通路之间的相互作用。我们最近对 人类乳腺癌数据库揭示了Wnt 2与其受体Frizzled 9的负相关性 （Fzd 9）和IGF-1 R表达。此外，在Wnt驱动的小鼠乳腺肿瘤中， IGF-1 R信号传导导致转移表型，我们还确定了Wnt 2和 Fzd 9表达。Wnt 2是Fzd 9的主要Wnt配体，并且该信号传导回路遵循Fzd 9的信号传导通路。 典型Wnt途径，其中Wnt 2与Fzd 9结合增加总β-连环蛋白的水平。 Wnt 2和Fzd 9的表达在几种不同类型的癌症中升高， Wnt 2促进乳腺癌中更具侵袭性、转移性的癌症表型的发展， 和结肠直肠肿瘤细胞。我们的初步数据进一步证实，Fzd 9是上调的， 人腔上皮MCF 7乳腺癌细胞系，抑制IGF-1 R后。Wnt 2表达 在癌症相关成纤维细胞（CAF）中有报道;我们的初步数据显示， 除了Fzd 9之外，人乳腺癌细胞还表达Wnt 2，这表明该信号传导回路 可以以旁分泌和自分泌的方式起作用。综上所述，这些数据为以下方面提供了依据： 我们的新假设是，乳腺癌中IGF-1 R水平降低导致激活增加， Wnt 2/Fzd 9信号环的一部分。这将通过以下两个具体目标进行检验： 1)确定Wnt 2/Fzd 9信号轴如何通过减少IGF-1 R信号调节， 定义负责Wnt 2表达的细胞组分。 2)研究Wnt 2/Fzd 9信号转导轴如何在以下背景下改变肿瘤细胞表型： 降低IGF-1 R功能。