Projects

Exploring hormone-receptor signaling

Hormones and hormone receptors play critical roles in regulating a multitude of normal cellular functions. However, many of these functions go awry in a variety of disease states and actually drive disease progression. Therapeutic targeting of these receptors is ideal given their intrinsic function as transcription factors and their natural ability to bind ligands.

Studies in the Molecular Analysis of Human Diseases Lab are aimed at understanding when, where and how receptors can and should be targeted in various diseases. Current areas of research encompass some of the topics highlighted on this page.

Functions of ERβ in breast cancer development and treatment

A major goal of our laboratory is to comprehensively understand the expression profiles and mechanisms of action of estrogen receptor beta (ERβ) in normal breast tissue and in the development of breast cancer. With support from the Mayo Clinic Breast Cancer SPORE and multiple foundations, including the Harold E. Eisenberg Foundation, we have developed novel cell and animal models, and have used thousands of patient samples to address multiple complex questions pertaining to this form of the estrogen receptor. Our findings have revealed that ERβ functions as a tumor suppressor in breast cancer and may actually prevent the development of breast cancer in some settings. Results from our studies have led to the development of a phase II clinical trial that will specifically examine the utility of therapeutically targeting ERβ for the treatment of triple-negative breast cancer.

Importance of endoxifen for the treatment of ERα+ breast cancer

In collaboration with Matthew P. Goetz, M.D., we characterized the relevance of endoxifen, a primary metabolite of tamoxifen, for the treatment of estrogen receptor alpha-positive (ERα+) breast cancer. Using laboratory models, we were able to demonstrate that endoxifen is primarily responsible for the anti-breast cancer effects of tamoxifen. We have described a number of the primary mechanisms by which endoxifen elicits its anti-cancer effects and have demonstrated how and why this metabolite behaves differently from the parent compound. We have developed the first models of endoxifen-resistant breast cancer and are devising approaches that could be implemented to overcome resistance to this drug. Ours studies help support the development and completion of a phase I and phase II clinical trials of endoxifen therapy for ERα+ metastatic breast cancer. These studies have been funded by the Mayo Clinic Breast Cancer SPORE and the Susan G. Komen organization.

Role of the glucocorticoid receptor in endocrine-resistant breast cancer

We have recently found that activation of the glucocorticoid receptor results in inhibition of multiple models of endocrine-resistant breast cancer. Through molecular profiling studies, we have identified a secreted protein called AZGP1 that is highly induced by the glucocorticoid receptor that functions to inhibit breast cancer cell proliferation and migration. With support from the Mayo Clinic Breast Cancer SPORE, studies are underway to elucidate the mechanisms of action by which this novel factor functions, including its expression profiles in normal and diseased tissue and how it, or related molecules, could be used as novel therapies for the treatment of advanced breast cancer.

Development of lestaurtinib for the treatment of ovarian cancer

Through the use of a small molecule library of epigenetic regulators, we identified lestaurtinib as a potent inhibitor of both chemotherapy-sensitive and chemotherapy refractory ovarian cancers. With support from the Mayo Clinic Ovarian Cancer SPORE, we have demonstrated that lestaurtinib can synergize with standard-of-care chemotherapy regimens and inhibit the growth of organoid models derived from ovarian cancer patients. We are in the process of identifying the primary pathways through which this drug functions and elucidating processes by which cancer cells can overcome the inhibitory effects of lestaurtinib during the course of treatment. Our primary goal is to develop the necessary preclinical data required for testing the efficacy of lestaurtinib in patients with advanced ovarian cancer.

Biological actions of TIEG/KLF10 in skeletal cells

In a project funded by a National Institutes of Health grant, we have identified TIEG/KLF10 as an estrogen-regulated gene in bone cells that is essential for the normal bone anabolic effects of estrogen in this tissue. Through a series of publications, we have identified central roles for this transcription factor in regulating the transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP) and Wnt signaling pathways and have shown that loss of KLF10 expression results in an osteopenic bone phenotype only in female mice. Ongoing studies seek to further understand the importance of TIEG in normal bone homeostasis and why this factor plays a more predominant role in maintaining bone mass in female animals compared with their male counterparts.

miRNAs and post-menopausal osteoporosis

With support from the National Institutes of Health, we have identified four specific microRNAs (miRNAs) that are suppressed after estrogen depravation and induced in response to estrogen-replacement therapy in a mouse model of postmenopausal osteoporosis. We have shown that these miRNAs contribute to the transcriptional effects of estrogen in bone cells and hypothesize that loss of expression of these miRNAs contributes to bone loss in the setting of estrogen depletion. Efforts are currently underway to understand the exact functions of these miRNAs in bone cells and determine if treatment approaches using a cocktail of these miRNAs could slow bone loss in postmenopausal models.

Importance of TIEG/KLF10 in skeletal muscle physiology

In collaboration with Sabine F. Bensamoun, Ph.D., we have shown that TIEG is highly expressed in skeletal muscle and that loss of TIEG expression results in severe defects in skeletal muscle architecture and function. Like the bone phenotype described above, this phenotype is strikingly only present in female animals. We have demonstrated that mitochondrial function is impaired in the skeletal muscle of TIEG knockout mice and have shown that this leads to exercise intolerance and a number of phenotypes that are characteristic of muscle myopathies in humans. Ongoing studies are aimed at identifying the primary pathways that are disrupted in the muscle of TIEG knockout mice and determining strategies that could be used to restore mitochondrial function and overcome these defects.