Lei Duan, MD, does basic and translational cancer research with a focus on understanding molecular mechanisms underlying cancer therapy resistance. For example, a current project is to study molecular mechanisms for anti-estrogen therapy resistance in estrogen receptor positive (ER+) breast cancer.
Lei Duan, MD, works closely with Carl Maki, PhD, as an integral group on several translational cancer research projects. One of the projects is to study how tamoxifen (TAM) resistance in ER+ breast cancer is regulated by prolyl peptidases such as prolylcarboxypeptidase (PRCP) and prolyl endopeptidase (PREP).
TAM is a selective estrogen receptor modulator (SERM) and standard endocrine therapy for premenopausal women with ER(+) breast cancer. For post-menopausal women, treatment includes a single aromatase inhibitor (AI) or TAM followed by an AI for extended periods. Despite these approaches, 40-80% of node-positive and 24-30% of node-negative cases recur with metastasis. Either de novo or acquired resistance contributes to poor prognosis in these patients.
Aberrant PI3K/AKT/mTOR activation is common in breast cancer and contributes to TAM resistance and metastasis. This pathway is activated downstream of receptor tyrosine kinases (RTKs) including IGF-1R, EGFR, and insulin receptor (IR). Ligand binding triggers RTK autophosphorylation and recruitment of the adaptor protein IRS-1. IRS-1 recruits PI3K p85 subunit to membrane and activates the PI3K pathway. AKT is downstream of PI3K and promotes survival by phosphorylating various pro- and anti-apoptotic factors. mTORC1 is activated downstream of AKT. Hyper-activation of the PI3K/AKT/mTOR pathway promotes endocrine therapy resistance and metastasis. IRS-1 expression decreases estrogen dependence, and IRS-1 knockdown sensitizes breast cancer cells to TAM. AKT induces TAM resistance in MCF7 cells through mTORC1. mTORC1 promotes cell motility and invasion in vitro and tumor metastasis in vivo in animal models.
Prolylcarboxypeptidase (PRCP) and its family member PREP are members of the prolyl-peptidase family. These enzymes cleave neuropeptide GPCR agonists to regulate GPCR signaling. PRCP was identified in a genetic screen for factors that promote TAM resistance in MCF7 cells. Subsequent studies found PRCP and PREP are critical for cell survival in a number of cancer cell lines of breast cancer, pancreatic cancer and lung cancer. PRCP and PREP are required for stability of IRS-1 and activation of PI3K/AKT. Current research in our lab is to understand how PRCP and PREP regulates IRS-1/2 stability and activation of PI3K/AKT pathway as well as other pathways downstream of IRS-1/2. The inhibitors of PRCP and PREP are also evaluated for their efficacy in killing cancer cells and suppressing tumor growth in animal models.
We use cell-based assays to study cancer cell signaling at mRNA and protein levels and action/mechanisms of anti-cancer agents. We also use immunohistochemistry (IHC) to evaluate prognostic protein biomarkers. In addition, we conduct tumor xenotransplantation in immunodeficient mice for evaluation of efficacy of anti-cancer agents.
Complete list of published work in My Bibliography.
Maki, Carl (PI)
TARGETING PROLYL PEPTIDASES IN TAMOXIFEN RESISTANT BREAST CANCER
This project is to study the mechanism underlying prolylpepdidase-regulated activation of PI3K-AKT-mTOR pathway, the effect of a prolylpeptidase inhibitor on treatment of endocrine resistant breast tumors and the prognostic value of prolylpeptidase expression in breast cancer patients.