Targeting a Novel Lipid Kinase Complex that Regulates Mutant p53 Stability in Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer defined by lack of three receptors (estrogen receptor, progesterone receptor, and HER2) that are commonly expressed in other types of breast cancer. TNBC often strikes young African-American and Hispanic women and spreads rapidly to the lungs and brain despite treatment. Unfortunately, there are no alternatives to chemotherapy for TNBC because these tumors lack the receptors that have been successfully targeted in other types of breast cancer. Hence, there is an urgent need to develop new therapies for this deadly disease. Two of the most common molecular abnormalities in TNBC are mutation of the p53 gene and expression of the cell stress protein aB-crystallin, both of which promote tumor growth and make tumor cells resistant to cell killing by chemotherapy. We have discovered that these two key growth regulators form a complex with another molecule called PIPKIa. This complex stabilizes mutant p53, allowing it to promote tumor growth. In addition, we have discovered that a drug that inhibits PIPKIa called ISA-2011B causes the destruction of mutant p53 and selectively kills TNBC cells. We hypothesize that this newly discovered complex is a key regulator of the aggressive biology of TNBC and that disrupting this complex with ISA-2011B will lead to the destruction of mutant p53, kill TNBC cells, and make them more vulnerable to chemotherapy drugs. This proposal addresses three of the Fiscal Year 2016 Breast Cancer Research Program Overarching Challenges, including revolutionizing treatment with less toxic and more effective options, eliminating the mortality of metastatic breast cancer, and identification of what drives tumor growth and how to stop it. We will test our hypothesis in three aims. In Aim 1, we will identify how each of the molecules in the mutant p53/aB-crystallin/PIPKIa complex bind to each other and regulate the stability of mutant p53. We will also determine the effects of inhibiting PIPKIa with genetic approaches and the drug ISA-2011B on the stability of the complex and identify how this leads to mutant p53 destruction in the cell. In Aim 2, we will investigate whether inhibiting PIPKIa in TNBC cells kills them and makes them more sensitive to chemotherapy drugs. In addition, we will examine the effect of ISA-2011B alone or in combination with chemotherapy on primary and metastatic growth in mouse models using TNBC cell lines and patient tumors with mutant p53. Mouse tumors will be examined to see if they undergo the same molecular changes that we observed in cultured TNBC cells. In Aim 3, we will take advantage of a unique existing breast tumor tissue bank (372 tumors) at the University of Wisconsin Carbone Cancer Center that has linked clinical data for each patient. Tumors will be examined for expression of mutant p53, aB-crystallin, and PIPK1a to see if these molecules are present in the same tumors and located near each other in the tumor cells. In addition, we will examine the association of these markers with patient survival and other clinical outcomes. Impact: Our project features a new collaboration between a basic scientist (Dr. Richard Anderson) and translational breast cancer researcher (Dr. Vincent Cryns) to translate an exciting new basic science discovery into a novel therapy (PIPKIa inhibitors) for poor-prognosis TNBC. We have discovered a new molecular complex composed of mutant p53, aB-crystallin, and PIPKIa, which regulates the stability of mutant p53, a key driver of the aggressive tumor biology of TNBC. This complex is a promising drug target for TNBC as we have demonstrated that inhibiting PIPKIa promotes destruction of mutant p53 and kills TNBC cells. As such, our findings could revolutionize treatment for TNBC by pointing to PIPKIa inhibition as new strategy for this deadly disease with few treatment options.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710258
Entities
People
- Richard A. Anderson
Organizations
- United States Army
- University of Wisconsin–Madison