Appointment period: 1/1/2013 to 9/5/2014

Project

Investigation of LRRC24, a putative negative regulator of ErbB receptor tyrosine kinases

Breast cancer is the most common cancer diagnosed in women with 1 in 8 being diagnosed in their lifetime. Breast cancer claims approximately 40,000 lives each year and is the second leading cause of death among women, second only to heart disease. Breast cancer treatment has been revolutionized through the development of targeted therapies such as Tamoxifen and Herceptin although therapeutic resistance is a persistent problem. Mechanistic insight into the regulation of oncogenic signaling pathways has provided a strong foundation for improving the therapy of breast cancer and other types of cancer. My research interests lie in understanding the regulation of the ErbB family of receptor tyrosine kinases (RTKs). Dys-regulation of the ErbB family, which includes EGF receptor (EGFR), ErbB2, ErbB3 and ErbB4, has been reported in nearly all types of solid cancer, including lung, prostate, brain and breast cancer. In breast cancer, the ErbB2 gene is amplified in ~ 25% of tumors, designated ErbB2-positive, managed through Herceptin containing regimens and in progressive disease, Lapatinib-containing regimens. Although ErbB2 has long been recognized as a “driver” gene in breast cancer and ErbB2-positive disease follows a particularly poor prognosis, very little is known of the endogenous mechanisms which restrict ErbB2 signaling. The Sweeney lab is interested in these mechanisms as they could be instructional for novel therapies.n the neural tube, brain, heart, and placenta. Fibroblasts isolated from DLC-1 mutant embryos contain disrupted actin filaments and fewer focal adhesions. The embryonic fibroblast study results confirmed the role of DLC-1 in regulating actin cytoskeleton and focal adhesion structures. However, the early lethality of DLC-1 null embryos limited further study on its role as a tumor suppressor. The tissue specific deletion of DLS-1 in mice will provide more information on its roles in various cancers and may provide good animal models for those relevant human cancers.

Lrrc24 is a 513 amino acid transmembrane protein with a domain organization very similar to Kekkon-1. Preliminary data from the Sweeney lab has revealed that Lrrc24 decreases ErbB receptor expression as efficiently as Lrig1 , strongly suggesting that Lrrc24 is a negative regulator of the ErbB family of RTKs. Furthermore, Lrr24 is expressed in the murine mammary gland and the epithelium of the healthy human breast but may be decreased in breast cancer Analysis of the Weigelt breast cancer dataset demonstrates that Lrrc24 expression inversely correlates with time to metastasis, suggesting that Lrrc24 could be a metastasis suppressor Furthermore, Lrrc24 is decreased in prostate adenocarcinoma compared to normal prostate Collectively, our preliminary data highlight several key features of Lrrc24 which suggest it could be an important growth suppressor including its ability to negatively regulate oncogenic ErbB RTKs, its expression in normal tissue in which ErbBs are expressed and its potential loss in cancer. I hypothesize that Lrrc24 is a novel negative regulator of the ErbB family of RTKs and that it functions to suppress ErbB-driven tumor cell proliferation, motility and/or invasion.