This project focuses on a mechanistic analysis of the transmembrane leucine-rich repeat protein Lrig1. Lrig proteins have recently emerged as novel modulators of membrane receptors with relevancy to mammary gland biology and tumorigenesis, including members of the ErbB pathway. The central hypothesis of this proposal is that Lrig1 plays a critical role in the post-transcriptional regulation of oncogenic receptors ad that perturbation of Lrig1 in breast cancer contributes to aberrant receptor expression, impacting tumor initiation and /or progression. In this proposal, we will focus our efforts on two independent aims which will expand our knowledge of the function of the Lrig1 in mammary gland biology and tumorigenesis.
In Aim 1, we will exploit the Lrig1 knockout mice to define the role of Lrig1 in mammary gland development and oncogene-driven tumor development.
In Aim 2, we will examine the role of Lrig1 in crosstalk between the estrogen receptor-a and ErbB2 with implications for endocrine resistance.
The proposed research will examine the role of the transmembrane leucine-rich repeat protein Lrig1 in mammary gland development and carcinogenesis. Lrig1 has recently emerged as a key post-transcriptional regulator of oncogenic receptors including ErbB2. Relatively little is known about the post-transcriptional regulation of receptor expression. Filling these knowledge 'gaps' may expose opportunities which can be exploited to improve breast cancer treatment.
|Rowson-Hodel, A R; Wald, J H; Hatakeyama, J et al. (2018) Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene 37:197-207|
|Wald, J H; Hatakeyama, J; Printsev, I et al. (2017) Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination. Oncogene 36:5158-5167|
|Hatakeyama, Jason; Wald, Jessica H; Rafidi, Hanine et al. (2016) The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3. Sci Signal 9:ra65|
|Yokdang, N; Hatakeyama, J; Wald, J H et al. (2016) LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene 35:2932-47|
|Morrison, M M; Williams, M M; Vaught, D B et al. (2016) Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth. Oncogene 35:1143-52|
|Simion, Catalina; Cedano-Prieto, Maria Elvira; Sweeney, Colleen (2014) The LRIG family: enigmatic regulators of growth factor receptor signaling. Endocr Relat Cancer 21:R431-43|
|Frietze, Seth; O'Geen, Henriette; Littlepage, Laurie E et al. (2014) Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha. BMC Genomics 15:520|
|Printsev, Ignat; Yen, Lily; Sweeney, Colleen et al. (2014) Oligomerization of the Nrdp1 E3 ubiquitin ligase is necessary for efficient autoubiquitination but not ErbB3 ubiquitination. J Biol Chem 289:8570-8|
|Rafidi, Hanine; Mercado 3rd, Francisco; Astudillo, Michael et al. (2013) Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3). J Biol Chem 288:21593-605|
|Fry, William H D; Simion, Catalina; Sweeney, Colleen et al. (2011) Quantity control of the ErbB3 receptor tyrosine kinase at the endoplasmic reticulum. Mol Cell Biol 31:3009-18|
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