Transcriptional Repression of Aggressive Phenotypes in Breast Cancer
Abstract
Although breast cancer is often referred to as a single disease, it in fact consists of multiple subtypes that are unique in their genetic makeup, yielding highly disparate clinical outcomes. Luminal and HER2+ tumors are associated with better patient outcomes due to their expression of specific receptors (estrogen, progesterone, and HER2 receptors) that render them sensitive to drugs like tamoxifen or Herceptin. In addition, they are more “differentiated,” meaning they retain some of the properties of the normal breast cells that they came from, including a lower ability to grow and leave the breast. In contrast, these therapies are ineffective in the more aggressive basal breast cancers that lack these receptors [i.e., triple-negative breast cancer (TNBC)], leaving patients with very poor prognoses. Basal tumors also have greater numbers of a specialized cell type known as cancer stem cells or CSCs. These cells are unique in that they have the ability to form new tumors by migrating, invading, and growing in normal tissues like the lung or brain. Thus, the high number of these cells in basal tumors contributes to their aggressive and metastatic character. We propose that identifying how cells can sustain the more differentiated and less metastatic nature of luminal tumors and suppress the stem cells in basal breast cancers would provide a path for ultimately changing aggressive cancers into less metastatic and more treatable tumors. I have identified a protein known as TLE3 that I found can turn off a set of genes that are very active in basal tumors and inactive in luminal tumors. I hypothesize that TLE3 is a major decision point for the level of malignancy of breast cancers. Supporting this postulate, I have found that the levels of TLE3 in breast cancers are highly predictive of whether a patient will suffer a recurrence or not, even when just considering the group of luminal tumors. I will test my hypothesis by genetically changing the levels of TLE3 in luminal and basal breast cancer cells and determine if this alters their ability to grow, migrate, invade, and metastasize. I will also identify all of the other genes in the cell that TLE3 controls. I will particularly focus on the ability of TLE3 to control the gene known as SOX9. SOX9 helps cells become cancer stem cells, and my experiments have revealed that TLE3 actively turns off SOX9. Thus, I will determine if its regulation of SOX9 is the reason why TLE3 makes cells have more or less malignant features. Completion of the proposed work will address two of the overarching challenges of the Breast Cancer Research Program: (1) Distinguish deadly from non-deadly breast cancers: Upon completing this proposal, I will have determined if and how TLE3 stimulates features of luminal breast cancer cells such as reduced growth, migration, invasion, and metastatic ability compared to basal breast cancer cells. If TLE3 can repress the malignant properties of breast cancers, this would provide foundational knowledge for using TLE3 or its target genes as markers to discriminate aggressive from non-aggressive tumors. (2) Identify why some breast cancers become metastatic: Breast cancer stem cells have the unique ability to promote metastases by forming new tumors in normal tissues. Studies proposed herein will reveal whether TLE3 can prevent cancer stem cells and how it accomplishes this. This will provide an avenue for the future development of new therapies that target the cascade of events controlled by TLE3 to reduce malignancy. In addition to revealing a central switch in controlling breast cancer aggressiveness, this project will support my transition to becoming an independent investigator in the field of breast cancer. My career goal is to discover ways to treat breast cancers by learning how they acquire their deadly properties. In other words, I want to know how cells lose their identity of being a normal cell to becoming malignant tumors
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810455
Entities
People
- Lindsey Anstine
Organizations
- Case Western Reserve University
- United States Army