Twist Maintains Stemness in Latent Breast Cancer Metastases Through a Novel Non-DNA-Binding Function Targetable with Small Molecules
Abstract
I must tell you a true story. My best and dearest lifetime friend telephones me to tell me his 35-year-old wife, mother of two, has been diagnosed with early-stage breast cancer. It is small, operable, found to be with little to no lymph node involvement and displays the markers that are always associated with good prognosis. In short, surgeons and oncologists call this an ?indolent tumor.? This was a relief to us all, but the patient decided nonetheless to be as aggressive as possible in order to ?be sure no cells get away.? This includes breast removal, node dissection, cytotoxic and hormonal adjuvant therapy, etc. She is given a clean bill of health and is considered ?cured? by our standards today. Eight years later she complains of chronic hip and back pain and goes to her doctor. She is found to have extensive recurrent tumor widely disseminated in spine and long bones with spots in liver and lung to which she was largely asymptomatic. Despite aggressive combination cytotoxic therapy, the recurrent tumor is resistant to everything and she succumbs to metastatic disease within 6 months. This is a tragic story from which both our families are still reeling. I hear this type of story so often it makes me ill. Unfortunately, late recurrence of breast cancers is increasing and accounts for a good fraction of mortality. We must find a way to detect and possibly prevent late recurrence. How does this happen? It is now known that malignant cells leave the primary tumor very early in tumor growth, in fact, likely before the tumor is clinically evident or palpable. A small fraction of these cells can travel through the blood system to distant organs and invade those organs. Instead of developing into a new metastatic tumor, they remain dormant, sometimes for years. These dormant cells do not proliferate, they are resistant to drugs, and they remain quiescent until reactivated through unknown mechanisms. We must find a way to identify and eradicate this population of dormant cells. We have worked on a protein in the breast cancer cell, Twist, which causes both early metastatic spread and, when it is expressed in metastatic cells, can make them enter the state of dormancy. It is unknown how Twist maintains dormancy. We have discovered what we think is a switch in Twist that mediates the dormant state. This proposal will seek to fully define the mechanism of how Twist does this. We will identify the other proteins in the breast cancer cell that binds to Twist and also solve the atomic structure of Twist when it is bound to essential proteins. The work here will set the stage for the possible identification of drugs that could modulate or attack the dormant phenotype. It is my laboratory?s long-term goal to discover ways to eliminate metastasis and dormant cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710506
Entities
People
- Iii Frank Rauscher
Organizations
- United States Army
- Wistar Institute