A major focus of the laboratory is understanding the role of estrogen receptor alpha (ERα) phosphorylation in regulating receptor function and the mechanisms by which signaling pathway kinases/phosphatases alter function. These studies identify phosphorylation fingerprints for ERα that will impact tumor growth, migration/metastasis and response to endocrine therapy. These studies will provide the mechanistic groundwork for rational design of preclinical therapeutic combinations of endocrine therapy with agents that block or activate specific kinase signaling pathways.
Experimental therapeutics for estrogen receptor negative breast cancer:
Although ER-negative breast cancer responds to conventional chemotherapy, patients relapse more frequently and have a worse prognosis compared to patients with ER-positive tumors. c-Src is an oncogenic non-receptor tyrosine kinase that is up-regulated in approximately half of all breast cancers. Unfortunately, single agent clinical Src inhibitors have produced very modest or no activity in clinical trials with breast cancer patients. KX-01 was developed as a ‘first in class’ peptidomimetic Src kinase inhibitor. Preclinical studies in the laboratory demonstrated that KX-01 treatment resulted in significant regression of ER-negative tumors and reduced metastasis to lung and liver in mouse xenografts. Remarkably, low dose KX-01 resulted in re-expression of ERα in ER-negative tumors and sensitization of these tumors to tamoxifen treatment.
Circadian regulation of estrogen receptor function:
The impact of circadian disruption on nuclear receptor function is unknown. Artificial light at night is classified as a "probable human carcinogen" that contributes to circadian disruption. Extending this concept to estrogen receptor function during circadian disruption, female nude rats implanted with “tissue-isolated” MCF-7 breast cancer xenografts were housed in light boxes at 12/light:12/dark or exposed to dim light (0.2 lux) during the dark phase. Exposure to dim light resulted in markedly increased tumor growth and de novo resistance to tamoxifen that coincided with elevation of specific ERα phosphorylation sites. These collaborative studies with Steven Hill, Ph.D. and David Blask, M.D./Ph.D. demonstrated that increased ERα phosphorylation is a direct outcome of circadian disruption.
Adipocyte stem cells in reconstructive surgery and soft tissue repair:
Adipocyte stem cells (ASCs) are present in adipose tissue and serve as precursors for mature adipocytes. Our research group is evaluating the use of ASCs in fat grafts for reconstructive surgery in breast and head/neck cancer patients. We found that the body mass index (BMI) of the patient donor profoundly impacts the viability, morphology and osteogenic differentiation of ASCs. Hypoxia that occurs in fat grafts markedly alters the ASC secretome and immunomodulation. Finally, ASCs stimulate metastasis of both breast cancer and head/neck tumors indicating caution when applying ASCs for reconstruction after tumor resection.
Metastatic breast tumor model developed from patient biopsies:
Metastatic breast cancer is the leading cause of death in breast cancer patients. We developed a reproducible, hetero-transplant breast tumor model derived from primary needle biopsies from patients diagnosed with primary invasive ductal carcinoma. Tumors formed in mice exhibited a highly metastatic phenotype and enhanced tumorigenesis during metastatic latency in bone marrow.