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.

Public Health Relevance

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.

National Institute of Health (NIH)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Sathyamoorthy, Neeraja
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
Krig, Sheryl R; Frietze, Seth; Simion, Catalina et al. (2011) Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ER?-positive breast cancer. Mol Cancer Res 9:1406-17
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
Semsri, Suwanna; Krig, Sheryl R; Kotelawala, Lakmal et al. (2011) Inhibitory mechanism of pure curcumin on Wilms' tumor 1 (WT1) gene expression through the PKC? signaling pathway in leukemic K562 cells. FEBS Lett 585:2235-42
Krig, S R; Miller, J K; Frietze, S et al. (2010) ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells. Oncogene 29:5500-10
Ingalla, Ellen Q; Miller, Jamie K; Wald, Jessica H et al. (2010) Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors. J Biol Chem 285:28691-7
Fry, William H D; Kotelawala, Lakmal; Sweeney, Colleen et al. (2009) Mechanisms of ErbB receptor negative regulation and relevance in cancer. Exp Cell Res 315:697-706
Workman, Heather C; Sweeney, Colleen; Carraway 3rd, Kermit L (2009) The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res 69:2845-52

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