Direct Regulation of Estrogen Receptor Transcription Activity by NF1
Abstract
Our original project on which the current proposal is based focuses on breast cancer that is estrogen receptor positive (ER+). ER+ breast cancer is the most common form of breast cancer that can affect as much as 80% of all the breast cancer patients. Although great progress has been made to use endocrine therapy to target ER in order to specifically treat these tumors, the majority of deaths from breast cancer still come from ER+ disease. The key problem is relapse due to endocrine therapy resistance. Therefore, the original grant has focused on identifying treatment resistance drivers by identifying DNA mutations in tumors from patients who experienced treatment resistance and comparing them with tumors from patients who survived. We thus identified a gene, NF1 (Neurofibromatosis type-1), which when inactivated in the cancer cells, approximately triples the risk of death from the disease. NF1 mutation is a familiar bad actor for cancer, and for decades it has been best known to control the cancer driver Ras. Broken NF1 allows Ras to remain stuck in the “on” position, activating a number of downstream growth and survival signaling pathways. However, we have made the surprising finding that regulating Ras is not the only function of NF1. NF1 can also check ER’s ability to turn on expression of growth, and possibly metastasis, genes. As such, when NF1 is lost, the growth of the cells is greatly increased from the combined actions of Ras and ER, which may explain why NF1 loss was so lethal in our patient cohort — almost every patient with an inactive NF1 died. Understanding how NF1 works is essential for how to treat ER+ breast cancer that carries NF1 deficiencies because we have uncovered combinations of Food and Drug Administration (FDA)-approved drugs that can shut down both the ER and the Ras pathways, leading to efficient inhibition of tumor growth in patient-derived mouse models. This Expansion Award will build on the success of the current study to further explore another function of NF1, besides endocrine therapy resistance, by focusing on metastasis, which has no cure. ER+ breast cancer preferentially metastasizes to the bone. We realized that NF1 loss may promote bone metastasis because when we examined genes uniquely upregulated when NF1 was lost, we found an enrichment of genes controlling a critical step in metastasis called epithelial to mesenchymal transition (EMT), as well genes that promoted bone turnover. Furthermore, in clinical data, NF1 mutations are highly enriched in metastatic ER+ breast cancer, as compared to early-stage breast cancer. Patients whose tumors have low copy number of the NF1 gene developed metastasis to the bone, but not to other organs, much sooner. Therefore, in this Expansion Award we will investigate the hypothesis that NF1 loss can promote bone metastasis by inducing a set of genes that are not normally expressed in breast epithelial cells. In Aim 1, we will identify those metastasis genes that are directly controlled by NF1. Bone metastasis is difficult to study because of the lack of experimental models. We have developed a system by injecting tumor cells into the iliac artery in mice, which allows the cancer cells to be carried by the circulation to colonize and grow in the bone in the hind limbs. In Aim 2, we will use this strategy to study how NF1-deficient breast cancer cells interact with the bone and whether the drugs we identified that can inhibit tumor growth can also block bone metastasis. The success of this study will lay the foundation for future testing of treatment strategies centering on NF1 in clinical trials because we focus on using FDA-approved drugs. Indeed, we are already in the process of launching a clinical trial, with pharma support for the drugs, to test our treatment strategy. This can take us a step closer to achieving the goal of achieving complete regression of ER-positive breast tumors after standard endocrine therapy so th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910527
Entities
People
- Eric Chang
Organizations
- Baylor College of Medicine
- United States Army