Multifaceted functions of WD40 repeat proteins:
WD40 repeat proteins are a large family of adaptor/scaffolding proteins that orchestrate diverse signaling networks to control a variety of cellular processes. We have been studying two WD40 repeat proteins, RACK1 and WDR26 that we identified as novel Gbg-interacting proteins. Our previous work showed that these two proteins act as positive and negative regulators of Gbg signaling, and that alternate interactions of these two proteins with Gbg control the signaling flow of Gbg to regulate leukocyte polarization and migration. Moreover, we found that upregulated WD40 proteins augments oncogenic signals that promote tumorigenesis and metastasis of breast and prostate cancers. To further understand the pathophysiological functions of these two proteins, we have generated mice carrying floxed RACK1 and WDR26 genes. Using these mice, we are currently investigating the role of these proteins in immune cell function, liver metabolism and prostate and breast cancer development.
Role of GPCRs in HER2+ breast cancer development:
G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors that represent the highly desirable drug targets for diverse diseases, including cancer. Despite their importance, our understanding of how GPCRs contribute to tumorigenesis and cancer progression remains limited, because there are over 350 non-sensory GPCRs and many of them are
aberrantly expressed in cancer cells. Our research aims to delineate the function and mechanisms of a subgroup of GPCRs, Gi/o-GPCRs, in regulating the self-renewal and tumorigenic activities of stem cell-like breast tumor-initiating cells (TICs). We focus on ErbB2/HER2-positive breast cancers, because they are highly aggressive and have poor prognosis. HER2-targeted therapy is the preferred treatment for these cancers but drug resistance is the major hurdle. We are testing the idea that targeting Gi/o-GPCRs can eliminate TICs and restore HER2+ breast cancer patient response to current therapeutics.
Targeting cancer stem cells:
Cancer stem cells (CSCs) are a small subpopulation of cells within tumors that possess characteristics of normal stem cells, i.e., self-renewal and differentiation into heterogeneous cell types found in the tumors. CSCs have been shown to be resistant to many current therapeutics, including radiation and chemotherapy, and thus contribute to tumor recurrence and metastasis. Therefore, CSCs represent attractive therapeutic targets for developing more effective therapies that control cancer and achieve more sustained clinical responses in patients.
Nowadays, a major challenge in the CSC field is their identification, isolation and characterization. CSCs are commonly characterized by the expression of cell surface markers associated with stem cells, such as CD24, CD133 and CD44. However, there are no universal markers that can be used to define CSC populations in different tumors. The lack of appropriate CSC markers has hampered our understanding of the mechanisms that regulate the stemness and drug resistance of CSCs, and the development of therapeutics that specifically target CSCs.
We recently found that a SORE6 fluorescence reporter system can be used to effectively identify CSCs overexpressing the key pluripotent transcription factors SOX2/OCT4, in prostate cancer cells. Moreover, we have developed a suicide gene construct to selective eradicate CSCs. Currently, we are conducting high throughput screen to identify small molecule inhibitors that specifically target CSCs. This study has the potential to uncover novel cancer therapeutics.
Identification of novel molecular determinants of endocrine therapies in cancer:
Over 75% of breast cancers are estrogen receptor (ER) positive. ER+ breast cancers are usually treated with adjuvant endocrine therapies (ETs), of which the most widely used is tamoxifen. In early-stage ER+ breast cancers, ETs are highly effective, but approximately 40% eventually relapse with ET-resistant and metastatic disease, and 50% of patients with metastatic disease do not respond to initial ETs. The molecular mechanisms underlying ET therapy resistance are not fully understood, which has limited the development of effective approaches for preventing and overcoming resistance.
A genome-wide screen is a powerful unbiased approach for uncovering novel molecular alterations that contribute to drug resistance and disease progression. We recently took advantage of a powerful genome-editing approach, the CRISPR-Cas9 system, to conduct a combination of in vitro/in vivo genome-wide screen in ER+ breast cancer. We have already identified a list of new candidate genes that may control endocrine resistance, tumor recurrence and metastasis. We are currently determining the role of these candidate genes in ER+ breast cancer progression and response to endocrine therapies, and elucidating the underlying mechanisms. Additionally, we are applying the similar screen to prostate cancer to identify genes contributing to cancer progression to castration resistance.