Direct Regulation of Estrogen Receptor Transcriptional Activity by NF1
Abstract
Growth of the vast majority of breast cancers is driven by the estrogen receptor (ER), and we have made great progress in using endocrine therapy to target ER in order to specifically treat these tumors. Despite this, the majority of deaths from breast cancer still come from ER-positive disease. The key problem is late relapse due mostly to endocrine therapy resistance. The main goal of this project is to investigate a specific resistance mechanism that is genetically encoded in some cancers so we can design specific therapies against it. Cancer cells in a tumor are not created equal, and this diversity in cancer cells gives some cancer cells the ability to escape treatment. To identify how these resistant cells differ from the regular tumor cells, we have analyzed all the gene changes in over 600 patients who were treated with standard hormonal therapy (tamoxifen) and were monitored for outcome for over 10 years. We thus identified a gene, NF1 (Neurofibromin 1), which when inactivated in the cancer cells, more than triples the risk of death from the disease -- by far the worst outcome of any gene variant in this study. NF1 mutation is a familiar bad actor for cancer -- when a patient inherits a broken NF1 gene, it promotes tumor formation -- neurofibromas, in neurons as well as a higher risk of breast cancer. The broken NF1 allows another well-known driver for cancer, Ras, to remain stuck in the "on" position, activating a number of downstream signaling pathways that promote abnormal cell growth. Moreover, 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 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 is so lethal to our original patient cohort -- almost every patient with an inactive NF1 died. In addition, our study may also explain why the development of some tumors (such as neurofibroma) are influenced by estrogen levels in the patient, even though the affected tissues are not known to be ER responsive. It is possible that the development of a wide range of NF1-deficient tumors is also driven by enhanced ER signaling, not just by enhanced Ras activity, and that these tumors, like ER-positive breast cancers, can also be treated by anti-estrogen agents. A key objective of this project is to fully define NF1 s biological properties with a focus on its newly identified role in ER regulation. We will not stop there, however. Our second objective is to design a therapy that rationally combines Ras and ER targeting with agents that are in active clinical investigation in order to establish a strategy to treat NF1-deficient breast cancers. The success of this study will lay the foundation for future testing of treatment strategies centering on NF1 in clinical trials, thus taking us a step closer to achieving the goal of achieving complete regression of ER-positive breast tumors after standard endocrine therapy so that relapse is prevented. Finally, we suggest that the impact of this project could go beyond ER+ breast cancers because NF1 is also lost in many other cancers such as colon and lung cancers where estrogen also has a postulated role in growth regulation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610538
Entities
People
- Eric Chang
Organizations
- Baylor College of Medicine
- United States Army