Research

Research in the Marker laboratory is focused on understanding the biology of the prostate gland at the molecular level. Interest in understanding the biology of the prostate is driven both by the fascinating nature of the developmental processes that function during organogenesis of the prostate and by the high incidence in humans of prostatic diseases including prostatic adenocarcinoma and benign prostatic hyperplasia. The Marker lab is particularly interested in the role of endocrine hormones and paracrine hormones in regulating the biology of prostatic epithelial cells during prostatic branching morphogenesis and during the progression of human prostate diseases.

One current project in the lab seeks to investigate the molecular basis of benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS). BPH is a highly prevalent condition in aging men that is frequently associated with LUTS. While the etiology of BPH and LUTS remain largely unclear, available data are consistent with the hypothesis that changing hormone levels in aging men and/or the reactivation of developmental growth-regulatory pathways are underlying causes of BPH and associated LUTS. In support of the potential role of steroid hormones in BPH and LUTS, our studies have shown that male mice treated with testosterone + estradiol (T+E2) at doses that mimic the hormonal milieu in aging human males developed benign enlargement of the prostate that was associated with the appearance of proliferating foci along the urethra that resembled developmental prostatic buds, changes in the morphology of the prostatic peri-urethral region, and a high incidence of urinary retention. The hormone-induced mouse model also exhibited gene expression changes in the prostate that have been reported to occur in human BPH. Ongoing studies in this area are collaborative effort within the U54 GEORGE M. O’BRIEN CENTER FOR BENIGN UROLOGY RESEARCH that brings together investigators from the University of Wisconsin-Madison Schools of Pharmacy, Medicine and Public Health, and Veterinary Medicine as well as investigators from the University of Massachusetts-Boston and the University of Texas-Southwestern.

A second project in the lab focuses on the role of the Growth Hormone (GH)/IGF-1 axis in prostate and breast cancers. We are using mouse genetics, human patient samples, and other preclinical models to investigate the role of the GH/IGF-1 axis in these cancers as well as the molecular mechanisms regulated by this pathway that contribute to cancer progression and chemotherapy resistance. Genetic and epidemiological studies in humans support the concept that the GH/IGF-1 axis contributes in some way to breast and prostate cancer initiation and/or progression. Studies using animal models have shown that mice and rats that lack functional GH or GHR have dramatically impaired progression of experimentally induced breast and prostate carcinogenesis indicating that an intact GH/IGF-1 axis is required for cancer progression. In addition, data from The Cancer Genome Atlas (TCGA) project also show increased GHR expression in prostate cancers with ERG-fusion genes or ETV1-fusion genes that represent about half of prostate cancer cases. Together with our recently published data that show dramatically increased tumor growth when mGhr is modestly overexpressed in prostate cancer xenografts, these data further support the concept that alterations in the GH/IGF-1 axis including increased GHR expression may directly contribute to prostate cancer progression. Our ongoing research in these areas are significant because they will clarify the best ways to employ pegvisomant, a GHR antagonist approved by the FDA for the treatment of acromegaly, or other agents targeting the GH/IGF-1 axis for the treatment of breast and/or prostate cancers. In addition, our ongoing studies will create a new clinically relevant mouse prostate cancer model that recapitulates genetic and gene expression changes commonly observed in human prostate cancer.