SUMO Inhibition Represses Mammary Oncogenesis Through Etv1
Abstract
Certain types of breast cancer, particularly the types that do not make estrogen receptor, are more difficult to treat, do not respond to hormonal therapy, and have a worse prognosis. Anti-estrogen drugs such as Tamoxifen can also be used to prevent breast cancers that make estrogen receptor, but no such preventative treatment is available for the aggressive types of breast cancer that do not make estrogen receptor, such as HER2-amplified (HER2+) and triple-negative breast cancer (TNBC). These more aggressive breast cancers that do not make estrogen receptor are more likely to occur in African American women, younger women of all races, and women with familial breast cancer. We have recently uncovered a cancer pathway that offers a novel treatment approach for aggressive, hormone-resistant breast cancer. There is a biochemical pathway in aggressive breast cancer cells called sumoylation, and this SUMO pathway modifies proteins that control the aggressive nature of these cancers. We found that inhibiting the SUMO pathway, either by eliminating the biochemical enzymes in the SUMO pathway or with drugs that block the SUMO pathway, stops cancer cells from forming tumors. To study why breast cancers develop in some women, we used a mouse model where the mice have activation of a gene called Neu that causes mammary cancer when the mice are about 4 months of age (young adult). Activation of the identical human gene, called ERBB2, causes an aggressive form of human breast cancer called HER2+ subtype. We created a new mouse genotype that has a knockout of the Ube2i gene that makes a protein called Ubc9, which is necessary for sumoylation. Knockout of Ube2i will inhibit the SUMO pathway. We bred mice to have activated Neu, so they should get mammary cancer, but when the mice also have knockout of Ube2i, none of the mice developed mammary cancer, even after a year. To try and figure out why this happens, we used a new technique that allows us to look at what is happening with individual cells from the mammary gland, allowing us to examine very early stages of breast cancer development. When the mice have the activated Neu gene, just after puberty they start to have growth of a pre-cancer cell type, which we named the Neu-mediated Expanded Luminal Progenitor (NELP). We found that this group of NELP cells also make the gene called Etv1, which is known to cause other human cancers. We also know that Etv1 controls other genes and the ability for Etv1 to turn on other genes is controlled by sumoylation. Our objective is to find out how inhibiting the SUMO pathway represses the formation of mammary cancer. The clues we have from our preliminary findings lead us to focus our work on understanding whether Etv1 is the missing link between the SUMO pathway and the cause of breast cancer. The goals of our proposal are to determine if sumoylation of Etv1 is causing mammary cancer in our mouse model (Aim 1), to see if sumoylation of Etv1 alters how it regulates other genes that drive breast cancer (Aim 2), and to see if new drugs recently introduced in clinical trials that inhibit SUMO and ETV1 will work in aggressive human HER2+ and TNBC (Aim 3). The proposed work will address several of the Overarching Challenges including: Prevent breast cancer (primary prevention); identify determinants of breast cancer initiation; identify what drives breast cancer growth and how to stop it; revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. The findings will be directly applicable to patients with aggressive, HER2+, and TNBC. We will test our hypothesis about the mechanism through which SUMO inhibition repressed tumor formation. This direction of study is important since it provides critical insight into treatment approaches that target mechanisms that drive cancer initiation and progression. In addition, we will test directly whether small molecule drugs currently in clinical trials that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110153
Entities
People
- Ronald Weigel
Organizations
- United States Army
- University of Iowa