Therapeutic Targeting of Nuclear Hormone Receptors in Neurofibromin/NF1-Depleted Breast Cancer
Abstract
Estrogen receptor (ER) determines female reproductive physiology, and up to 80% of breast tumors are driven by ER. Conversely, the androgen receptor (AR) determines male reproductive physiology and is a major therapeutic target for prostate cancer. Despite this obvious dichotomy at the molecular levels, ER and AR are in fact closely related and are classified as sisters/brothers in the same family of steroid hormone receptors. They have similar protein structures and function in similar ways as ligand-dependent transcription factors to regulate gene expression. Importantly, AR is commonly co-expressed with ER in breast cancer, and up to 20% breast cancers lacking ER still express AR. The AR in breast cancer is biologically active, which results in intriguing therapeutic opportunities. In ER+ tumors, AR activation by testosterone can inhibit tumor growth. However, testosterone creates virilizing side effects in women, limiting its use. This problem is being addressed by the use of selective androgen receptor modulators (SARMs, e.g., enobosarm) with fewer side effects, and SARMs are now in clinical trials to treat ER+/AR+ breast cancer. In contrast, in ER- tumors, AR activation can promote tumor growth, and drugs that inhibit AR activity (e.g., enzalutamide) are in clinical trials to treat AR+ triple-negative breast cancer with promising early results. This new study centers on the key tumor suppressor called neurofibromin and its important interactions with both ER and AR. Neurofibromin is the product of the NF1 gene, which is frequently mutated in a wide range of cancers including breast cancer. Previously, neurofibromin was best known as a brake that blocks the function of a potent cancer driver called Ras. Thus, when neurofibromin is inactivated, tumor formation was assumed to be driven by the release of Ras activity. However, NF1 mutations that selectively inactivate neurofibromin’s Ras-suppressing function are very rare in primary breast cancer. Instead, we have shown that NF1 “null-like” mutations, which result in loss of the whole neurofibromin, are more frequent in breast cancer and correlate with very poor outcome after adjuvant tamoxifen or aromatase inhibition treatment. Moreover, NF1 mutations are enriched in metastatic breast cancer. These results have led to the discovery of a new neurofibromin function, totally independent of its Ras interaction, that drives breast disease toward a more aggressive state. In a previous DoD-sponsored project, we have demonstrated that neurofibromin can bind ER directly to repress its ability to control gene expression. When neurofibromin is lost, ER-dependent gene expression is greatly increased so that the cell can grow in very little estrogen or even in tamoxifen, explaining the poor outcome seen in patients. The only clinically available endocrine agent that still works, at least initially, is fulvestrant, which lowers ER protein levels by promoting its degradation. However, when ER+ breast cancer cells lose their ER, their survival becomes fully dependent on Ras, which is made more active when neurofibromin is lost. We determined that the Ras activity can be inhibited using FDA-approved drugs that block a key component downstream of Ras called MEK. Thus, fulvestrant plus a MEK inhibitor (MEKi, e.g., binimetinib) can induce full tumor regression in a patient-derived xenograft (PDX) model derived from a patient who failed several lines of endocrine therapy. For personalized medicine to work, we must target the specific pathways that are driving the cancer, and in the case of NF1- tumors, our data conclude that we must use an endocrine agent plus a MEKi. Now, consistent with the concept that ER and AR are closely related, we have evidence supporting the hypothesis of this proposal that neurofibromin is also an AR repressor, so that neurofibromin loss is expected to greatly increase AR activity. The overall objective of this project is to investigate this hypothesis in ord
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110107
Entities
People
- Matthew J Ellis
Organizations
- Baylor College of Medicine
- United States Army