Requirement of EHD1/2-Dependent Membrane Repair for Triple-Negative Breast Cancer Metastasis
Abstract
Challenges Addressed: (1) Identify why some breast cancers become metastatic. (2) Identify what drives breast cancer growth; determine how to stop it. Nearly a quarter million women will be diagnosed with breast cancer this year in the US alone, and about 40,000 will die of their disease. Approximately 2.8 million American women currently live with breast cancer. Most of these survivors will die prematurely, nearly 95% of those diagnosed at younger ages; in almost all cases, death is due to metastatic disease. 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 (TNBC) and HER2/ErbB2+ subtypes of breast cancer are substantially more metastatic. While targeted therapies against the HER2+ cancers have helped prolong the survival of ErbB2+ patients, targeted agents are lacking for TNBC. TNBC deaths are more common among African Americans, accounting in part for their higher death rate from BC despite a lower overall incidence (www.acs.org). A better understanding of cellular adaptations that make tumor cells metastatic 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 in case of emergency. Damage to a cell’s outer membrane represents such an emergency. 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 are more prone to damage their outer membranes -- meaning that they live in a higher state of emergency. To cope with this inherent problem of metastasis, they activate the same deployment mechanisms that our muscle cells use normally. We have found that key components of this pathway, members of a protein family we call EHD proteins, are expressed at increased levels in breast cancers, and such increased expression correlates with metastasis and shorter survival chances of a patient. Experimentally, we find that suppressing the expression of one of the EHD proteins eliminates the ability of metastatic tumor cells to grow tumors and to metastasize to lungs of experimental animals. We have made 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 as experimental animal models. Thus, the current project represents a shift in the current paradigm of our understanding of metastatic breast cancer. While our current studies are conducted at a basic cancer biology level, there is a strong possibility that a successful validation of our hypotheses can lead to a relatively rapid translational impact. Our short-term goal is to prove that the proteins we have discovered, as well as their associate proteins, indeed regulate metastatic properties of TNBC cells. The long-term goal is to then leverage
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710616
Entities
People
- Hamid Band
Organizations
- United States Army
- University of Nebraska Medical Center