Yan Zuo, PhD

Areas of Interest

Research Interests

Investigate the in vivo roles of Net1 in breast cancer and vascular injury

Net1 is a RhoA specific guanine nucleotide exchange factor that is overexpressed in numerous human cancers including gastric adenocarcinoma, hepatocellular carcinoma, gliomas and breast cancer . In prior work we have shown that co-expression of Net1 with α6β4 integrin is prognostic for reduced metastasis-free survival in estrogen receptor positive breast cancer patients. Furthermore, we and other groups have shown that Net1 expression, especially the Net1A isoform, is required for breast cancer cell migration and invasion  and epithelial-mesenchymal transition. Moreover, data from our newly generated NET1 knockout mouse model indicates that Net1 deficiency slows normal mammary gland development by inhibiting ductal extension and branching. This is accompanied by reduced phosphorylation of regulatory myosin light chain, an indicator of RhoA activity, and increased collagen deposition. Net1 deficiency also leads to disorganization of myoepithelial and ductal epithelial cells and impaired estrogen receptor (ERa) expression and signaling. These data indicate that Net1 plays an important role in controlling the proliferation and migration of mammary epithelial cells in the developing mammary gland. To ascertain the role of Net1 in breast tumorigenesis and metastasis, we are breeding NET1 knockout mice with MMTV-PyMT and MMTV-Her2 mouse models of breast cancer.

RhoA activation is a critical event in the development of vascular inflammatory disease. Since Net1 is an important regulator of RhoA activation and motility in cancer cells, we hypothesize that NET1 may also regulate vascular disease by controlling vascular smooth muscle and leukocyte motility after vascular injury. We will study whether NET1 KO will prevent neointima formation after vascular injury. We will also assess whether NET1 KO inhibits vascular smooth muscle proliferation and /or migration in vitro, as well as the recruitment of inflammatory cells to injured region. To study the role of Net1 in vascular injury a carotid artery ligation model was chosen. Preliminary data indicate that genetic deletion of NET1 mice inhibits neointima formation, by preventing macrophage infiltration of the injured area and inhibiting vascular smooth muscle cell proliferation and motility. Identification of a role for Net1 in vascular disease will define an important new regulator of RhoA signaling in vascular disease, and provide a novel molecular target for therapeutic intervention.

Publications