Targeting a Novel EHD2-SOCE Prometastatic Axis in TNBC
Abstract
Well over 270,000 Americans (99% of them women) will be diagnosed with breast cancer this year in the US alone, and about 42,000 will die of their disease. Thanks to reduced overall mortality due to earlier diagnosis of early-stage breast cancers and better management of local/regional breast cancers, 2.8 million Americans currently live with breast cancer. Thankfully, most survivors will have a long remission and even a normal cancer-free life. Unfortunately, 20%-30% of these patients will recur with an incurable metastatic (stage III or IV) disease. In addition, 6%-10% of new patients present as stage IV disease. Metastatic disease is the primary cause of death from breast cancer, accounting for as many as 90% of all deaths. Reducing the burden of death from metastatic BC is an urgent and unmet need. Metastases arise when cells in the original (primary) breast tumor of a patient acquire certain key adaptations that allow them to invade the surrounding tissues, leave the tumor nest and take residence in another organ. These nomadic cells give rise to metastasis, and signify a critical transition in a tumor towards the destruction of the host, unfortunately resulting in the death of a breast cancer patient. Key approaches of surgery and radiation are unfeasible against metastatic tumors, thus limiting the avenues available to a patient to chemical/biological therapies alone. Unfortunately, metastatic tumors are commonly resistant to anti-cancer drugs or become so soon after therapy. Drugs to directly target the mechanisms of “metastasis” are currently lacking. Triple-negative breast cancer (TNBC; one that lacks estrogen and progesterone receptors and HER2 marker) is substantially over-represented in the metastatic group, and targeted agents are still lacking for TNBC, together accounting for a particularly high death burden associated with this subtype of BC. TNBC deaths are more common among younger patients and African Americans, accounting in part for the >40% higher death rate of African American women from BC despite lower overall incidence (www.acs.org). A better understanding of pro-metastatic cellular adaptations can open new molecular avenues to combat the lethality of metastatic TNBC, and potentially all metastatic breast cancers. The investigators have been working on a basic cell biological pathway that helps controls the type and quantity of proteins that are displayed on the outer membranes of cells – akin to a fundamental national defense function that controls the number and type of personnel at our nation’s borders, as well as how rapidly they might be deployed when needed. Recent work has revealed that tumor cells that gain metastatic behaviors and begin to move restlessly through tissues and blood vessels to go to distant sites use certain biochemical pathways excessively and can thus become dependent on these pathways. This can become an Achilles heel of such metastatic tumor cells. We have found that a key component of this pathway, member of a protein family we call EHD proteins, is expressed at increased levels in breast cancers especially in TNBC, and such increased expression correlates with metastasis and shorter survival chances of a patient. Experimentally, we find that suppressing the expression of this EHD protein eliminates the ability of metastatic tumor cells to grow tumors and to metastasize to lungs of experimental animals. We have now linked the function of EHD2 in increasing metastatic behavior of TNBC tumor cells to a biochemical pathway involving proteins (called STIM1 and Orai1) that control the entry of calcium into cells through a process called SOCE. SOCE in turn is critically important for metastatic behaviors. Here, we propose innovative cellular, molecular, and animal model tools to directly establish if the pathway we have discovered is indeed a crucial mediator of a tumor cell’s metastatic behavior, conducting experiments at the level of cells as well a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010058
Entities
People
- Hamid Band
Organizations
- United States Army
- University of Nebraska Medical Center