Breast cancer is a complex disease that kills patients by invading adjacent tissue and spreading to other organs in a process called metastasis. The disease affects about one in every seven women and accounts for over 40,000 deaths in the United States each year, the vast majority of which are due to deadly spread of metastatic cancer cells to organs such as bone and lung. While prevention, diagnosis, and therapy of breast cancer are improving steadily due to intense research and clinical efforts, we are still far from being able to prevent the development of metastatic relapse in early-stage patients or cure advanced late-stage breast cancers. Improved treatments critically rely on better understanding of the molecular mechanisms driving breast cancer recurrence and metastasis.

We began to tackle this question by using powerful computational approaches to analyze the genomic data of breast cancers with different outcomes. We identified a gene called Metadherin (MTDH) that is present at abnormally high level in patients who have more dangerous (poor-prognosis) breast cancers that are prone to relapse and metastasis. We next used genetically modified mouse models and human patient-derived xenograft to discover an essential and universal role of MTDH in supporting the initiation of diverse subtypes of breast cancers. The ability of MTDH to support the survival of breast cancer stem cells under oncogenic stress explains why more than 40% of breast cancers have abnormally high levels of MTDH in the primary tumor and why these tumors have high risk of generating metastasis. As an important step toward targeting MTDH for breast cancer treatment, we have also resolved the crystal structure of MTDH with its functional partner SND1 in a collaborative effort with the Partnering Principal Investigator (PI), Dr. Yongna Xing, at the University of Wisconsin - Madison.

The proposed study will build on these exciting and ground-breaking discoveries to answer the following key questions that are required to develop new MTDH-targeting treatments: (1) How does MTDH-SND1 protect cancer cells under various stress conditions? (2) Is MTDH required in different stages of breast cancer progression, especially in late-stage metastatic disease? (3) Can we identify small chemical molecules that disrupt the interaction between MTDH and SND1? (4) What is the therapeutic consequence of treatment of breast cancer with such compounds? The proposal is built upon the perfect combination of expertise and research experience of two partnering investigators. Dr. Yibin Kang, the Initiating PI and a former Breast Cancer Research Program Era of Hope Scholar, is an expert in the study of breast cancer metastasis. Dr. Yongna Xing, the Partnering PI, is an expert in the structural biology of cell signaling complexes related to cancer, and she has a long and productive history of collaborative research with Dr. Kang in the study of MTDH-SND1. The research team will also benefit from the extensive and unique experience of Dr. Hahn Kim and Dr. Scott Wildman in ultra-high-throughput screening and chemical biology approaches in drug development.

The proposed studies are expected to be completed within 3 years, with two important end products: (1) proof-of-concept evidence that MTDH is a suitable target for the prevention and/or treatment of metastatic breast cancer and (2) identification of lead chemical compounds with therapeutic potentials that can be further developed into novel therapeutics for breast cancer patients. The project will therefore address the following Overarching Challenges: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Identify why some breast cancers become life-threatening metastasis. (3) Revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. (4) Eliminate the mortality associated with metastatic breast cancer.

Over 90% of breast cancer-related deaths are due to inoperable relapsed tumors in distant vital organs that resist conventional chemotherapies. Our proposed studies will provide novel insights into the molecular mechanism of MTDH and its functional partner SND1 in tumor initiation, progression, metastasis, and chemoresistance of breast cancer. Furthermore, our research will facilitate the development of novel anticancer therapeutics based on molecular targeting of MTDH and SND1. The proposed study will identify the specific functional roles and signaling networks of the MTDH-SND1 interaction in tumor promotion, metastasis, and chemoresistance and will evaluate the therapeutic potential of targeting the MTDH-SND1 interaction using genetic ablation and novel small molecule inhibitors. Results from these studies may lead to the development of new therapeutic strategies to prevent or reduce chemoresistant metastasis of breast cancer and benefit over 40% of breast cancer patients who have tumor with high level of MTDH expression.