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

目前的研究是对一项关于什么监管基础和 三阴性乳腺癌的转移表型及其功能的研究 胰岛素样生长因子1型受体(IGF-1R)。拟议的补充研究 该项目将延长与父母资助的目标1相关的研究，这些研究旨在调查 IGF-1R与Wnt信号通路的相互作用。我们最近对 人类乳腺癌数据库显示Wnt2及其受体Frizzled9呈负相关 (Fzd9)和IGF-1R表达。此外，在Wnt驱动的小鼠乳腺肿瘤中， IGF-1R信号导致转移表型，我们还发现Wnt2和Wnt2增加 Fzd9表达。Wnt2是Fzd9的突出的Wnt配体，这个信号环遵循 典型的Wnt途径，其中Wnt2与FZD9结合增加了总β-连环蛋白的水平。 Wnt2和Fzd9在几种不同类型的癌症中表达升高，包括乳腺癌、 Wnt2促进乳腺更具侵袭性和转移性的癌症表型的发展 和结直肠肿瘤细胞。我们的初步数据进一步证实，Fzd9在 抑制IGF-1R后的人乳腺癌细胞株MCF7。WNT2表达式 已在癌症相关成纤维细胞(CAF)中被报道；我们的初步数据显示，一些 人乳腺癌细胞除表达Fzd9外，还表达Wnt2，提示该信号环 既可以旁分泌，也可以独分泌。综上所述，这些数据为 我们的新假设：乳腺癌中IGF-1R水平降低会导致激活增加 WNT2/Fzd9信令环路。这将通过以下两个具体目标来检验： 1)确定WNT2/Fzd9信号轴如何由减少的IGF-1R信号调节，以及 定义负责WNT2表达的细胞组件。 2)研究WNT2/Fzd9信号轴是如何改变肿瘤细胞表型的 减少了IGF-1R功能。

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.