Special Interests:Vitamin D chemoprevention and mechanism of resistance Prostate cancer, initiation, progression and castration recurrent disease Preclinical testing novel therapeutic approaches in animal models (transgenic and xenograft) LSD1 as a corepressor and coactivator of the vitamin D receptor Serotonin receptor signaling axis as a therapeutic target in prostate cancer
About Barbara Foster
Roswell Park Comprehensive Cancer Center
- Professor of Oncology
- Director, Experimental Therapeutics Graduate Program
- Member, Genitourinary Disease Site Research Group (GU TRG)
- Scientific Director, Experimental Tumor Model Resource (ETM)
- Director, Rapid Tissue Acquisition Program (RTAP) Core
- Member, Institutional Biosafety Committee (IBC)
- Member, Shared Resource Director Committee
- Department of Pharmacology and Therapeutics
Education and Training:
- Post-doctoral Fellow - Department of Cell Biology - Baylor College of Medicine, Houston, TX
- PhD - Anatomy - University of California-San Francisco, San Francisco, CA
- Society for Basic Urological Research (SBUR)
- American Urological Association (AUA)
Our laboratory uses animal models to understand the molecular mechanism of prostate cancer initiation and progression in order to rationally design therapeutic approaches for the prevention and treatment of the disease. The ultimate goal of the laboratory is to use preclinical testing of putative therapeutic agents to rapidly identify promising effective agents and facilitate the rapid movement of these compounds from the benchtop to the bedside.
The current focus of the lab is on understanding the molecular mechanism underlying corruption of vitamin D signaling in prostate cancer (PCa) progression and the impact of the serotonin 2C receptor (5HT2cR)/HBII-52 axis in PCa. Transgenic adenocarcinoma of mouse prostate (TRAMP) is used as a model of progressive PCa. The lab identified vitamin D (calcitriol) as a chemopreventive agent for primary PCa in hormone-intact TRAMP mice. However, long-term treatment of TRAMP mice with calcitriol increased the incidence of metastatic lesions. These studies suggest that early intervention with vitamin D can slow androgen-stimulated tumor progression, but prolonged treatment may result in development of a resistant and more aggressive disease associated with increased distant organ metastasis. LSD1 was identified as both a coregulator and coactivator of the vitamin D receptor. Current studies focus on understanding VDR/LSD1 in complex with other transcriptional regulators as determinants of transcriptional output in the context of the epigenome.
Another project in the lab has identified the small nucleolar RNA (snoRNA), MBII-52 (human homolog: HBII-52) as a potential marker and driver of castration-recurrent (CR) PCa. HBII-52 affects processing (A-to-I RNA editing and RNA splicing) of the serotonin 2c receptor (5HT2cR) pre-messenger RNA, which results in expression of isoforms of the 5HT2cR that are more active, and in some cases constitutively active (i.e. signal independent of ligand binding). These activated isoforms propagate a cascade of downstream signaling events that involves numerous pro-proliferative and pro-invasive target pathways, which include extracellular signal-regulated kinase (Erk) and RhoA. Mouse models of PCa (e.g. TRAMP, Pten-/-), a panel of human PCa cell lines, and clinical samples demonstrated that the putatively brain-specific snoRNA HBII-52 is elevated in PCa and correlates with aggressiveness, clinical outcomes, and development of the neuroendocrine phenotype. Thus, HBII-52 may provide a biomarker for PCa, the HBII-52 -> 5-HT2cR axis may represent a druggable target for aggressive and CR- PCa. We propose a model of PCa progression in which HBII-52 modulates editing and splice-site selection of the 5HT2cR pre-mRNA to produce a constitutively active isoform 5-HT2c-INIR. This isoform aberrantly activates downstream oncogenic signaling pathways (Erk and RhoA) and correlates with poor differentiation or the emergence of a neuroendocrine phenotype, thereby contributing to cancer progression. This pathway could be effectively treated by repositioning currently available selective inhibitors of 5HT2cR.
This work has been supported by National Institute of Health RO1, Department of Defense, American Italian Cancer Foundation, and RPCI Alliance Foundation.
- The GTEx Consortium (Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, Hasz R, Walters G, Garcia F, Young N, Foster B, Moser M, Karasik E, Gillard B, Ramsey K, Sullivan S, Bridge J, Magazine H, Syron J, Fleming J, Siminoff L, Traino H, Mosavel M, Barker L, Jewell S, Rohrer D, Maxim D, Filkins D, Harbach P, Cortadillo E, Berghuis B, Turner L, Hudson E, Feenstra K, Sobin L, Robb J, Branton P, Korzeniewski G, Shive C, Tabor D, Qi L, Groch K, Nampally S, Buia S, Zimmerman A, Smith A, Burges R, Robinson K, Valentino K, Bradbury D, Cosentino M, Diaz-Mayoral N, Kennedy M, Engel T, Williams P, Erickson K, Ardlie K, Winckler W, Getz G, Deluca D, Macarthur D, Kellis M, Thomson A, Young T, Gelfand E, Donovan M, Meng Y, Grant G, Mash D, Marcus Y, Basile M, Liu J, Zhu J, Tu Z, Cox NJ, Nicolae DL, Gamazon ER, Im HK, Konkashbaev A, Pritchard J, Stevens M, Flutre T, Wen X, Dermitzakis ET, Lappalainen T, Guigo R, Monlong J, Sammeth M, Koller D, Battle A, Mostafavi S, McCarthy M, Rivas M, Maller J, Rusyn I, Nobel A, Wright F, Shabalin A, Feolo M, Sharopova N, Sturcke A, Paschal J, Anderson JM, Wilder EL, Derr LK, Green ED, Struewing JP, Temple G, Volpi S, Boyer JT, Thomson EJ, Guyer MS, Ng C, Abdallah A, Colantuoni D, Insel TR, Koester SE, Little AR, Bender PK, Lehner T, Yao Y, Compton CC, Vaught JB, Sawyer S, Lockhart NC, Demchok J, Moore HF.) The Genotype-Tissue Expression (GTEx) Pilot Analysis: Multi-Tissue Gene Regulation in Humans. Science, 2015 (accepted).
- Ajibade AA*, Kirk JS*, Karasik E, Gillard B, Moser MT, Johnson CS, Trump DL, Foster BA. Early Growth Inhibition Is Followed by Increased Metastatic Disease with Vitamin D (Calcitriol) Treatment in the TRAMP Model of Prostate Cancer. PLOS One 2014, Feb 26; 9(2): e89555. doi:10.1371/journal.pone.0089555.
- The GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013 May 29;45(6):580-5. doi: 10.1038/ng.2653.
- Kwon ED*, Foster BA*, Hurwitz AA, Madias CM, Allison JP, Greenberg NM, and Burg MB. Elimination of residual metastatic prostate cancer following surgery and adjunctive CTLA-4 blockade immunotherapy. PNAS 2000; 96:15074-15079.
- Kaplan-Lefko PJ, Chen T, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ, Maddison LA, Foster BA, Greenberg NM. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. The Prostate 2003; 15;55(3):219-37.