Bruce Blumberg
Developmental & Cell Biology
School of Biological Sciences
Phone: (949) 824-8573
Email: blumberg@uci.edu
blumberg.bio.uci.edu
http://www.faculty.uci.edu/profile.cfm?faculty_id=4539
Bruce Blumberg
Researchers in the Blumberg laboratory study a family of ligand-modulated transcription factors, the nuclear hormone receptors, and their role in development, physiology and disease. Two receptors are particularly relevant to cancer – the retinoic acid receptors, RARs, and the steroid and xenobiotic receptor, SXR.
One long-standing interest in the laboratory concerns the interactions between nuclear receptor and growth factor signaling in important developmental patterning processes. Retinoic acid (RA) and fibroblast growth factors (FGFs) are critical factors that interact to mediate a variety of developmental processes. RA and FGF pathways are mutually inhibitory and this inhibition is important for key developmental processes and the proliferation of stem cells and cancer cells. The Blumberg lab seeks to understand the genetic program and molecular interactions underlying the mutual antagonism between RA and FGF signals. Dr. Blumberg’s laboratory has shown that RA regulates gene expression along the entire anteroposterior neural axis, instead of just the mid/hindbrain as had previously been thought. He has also identified RA target genes in early Xenopus embryo, most of which are expressed in the neural tissue.
Dr. Blumberg’s laboratory is also investigating the molecular basis of gene environment interactions. Their work concerns the nuclear steroid and xenobiotic receptor, SXR. A key feature of SXR is that its pharmacology differs among mammals and thus the response to environmental insults may be different in man vs mouse. For example, isoflavone phytoestrogens selectively activate human SXR, whereas certain polychlorinated biphenyls (PCBs) activate rodent SXR but antagonize human SXR. This suggests that these compounds will have significantly different effects in rodents and humans and that the results of studies on such compounds utilizing rodents may not be fully applicable to humans. Furthermore, SXR shows genetic variation among humans in that a number of sequence polymorphisms have been identified that alter the function of this receptor. Thus, differences in SXR may underlie at least some of the known differences among individuals in their ability to metabolize drugs and chemicals. Understanding how the xenobiotic response differs between individual humans, different animal species or even among different laboratory strains of the same species is essential to developing high quality models of the risk from chemical exposure. It will also aid in understanding how drug therapy for a variety of diseases can be tailored to individuals for maximum efficacy.
Two key findings about SXR related to cancer were recently made in the Blumberg laboratory. The first showed that SXR loss-of-function led to increased activity of the transcription factor NF-κB and consequent widespread inflammation in young animals. Older animals had numerous, apparently lymphoid tumors in the liver, intestine, spleen and pancreas. Preliminary results suggest that these are B-cell derived. Since SXR is a key mediator of the xenobiotic response, compounds that modulate its activity can have profound effects on inflammation and cancer. Research is underway to reveal the molecular mechanisms through which SXR and NF-κB inhibit each others’ activity.
Secondly, Dr. Blumberg’s laboratory showed that activation of SXR in breast cancer cells led to cell cycle arrest and apoptosis. In estrogen receptor positive, p53 wild type cells (e.g., MCF-7, ZR-75-1), activation of SXR led to induction of iNOS, stabilization of p53, induction of p53 target genes such as p21, BAX and puma then in cell cycle arrest and apoptosis. Preliminary results in estrogen receptor negative, p53 mutant cells show that these also undergo apoptosis in response to SXR activation but that the mechanism is different. Current research asks whether the observations on cultured cells can be translated to in vivo studies.
Selected Publications:
Shiotsugu, J., Katsuyama, Y., Arima, K., Baxter, A., Koide, T., Song, J., Chandraratna, R. A., and Blumberg, B. (2004). Multiple points of interaction between retinoic acid and FGF signaling during embryonic axis formation. Development 131(11), 2653-67.
Arima, K., Shiotsugu, J., Niu, R., Khandpur, R., Martinez, M., Shin, Y., Koide, T., Cho, K. W., Kitayama, A., Ueno, N., Chandraratna, R. A., and Blumberg, B. (2005). Global analysis of RAR-responsive genes in the Xenopus neurula using cDNA microarrays. Dev Dyn 232(2), 414-31.
Grun, F., Watanabe, H., Zamanian, Z., Maeda, L., Arima, K., Cubacha, R., Gardiner, D. M., Kanno, J., Iguchi, T., and Blumberg, B. (2006). Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol 20(9), 2141-55.
Zhou, C., Tabb, M. M., Nelson, E. L., Grun, F., Verma, S., Sadatrafiei, A., Lin, M., Mallick, S., Forman, B. M., Thummel, K. E., and Blumberg, B. (2006). Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest 116(8), 2280-2289.
Miki, Y., Suzuki, T., Kitada, K., Yabuki, N., Shibuya, R., Moriya, T., Ishida, T., Ohuchi, N., Blumberg, B., and Sasano, H. (2006). Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66(1), 535-42.
Kumagai, J., Fujimura, T., Takahashi, S., Urano, T., Ogushi, T., Horie-Inoue, K., Ouchi, Y., Kitamura, T., Muramatsu, M., Blumberg, B., and Inoue, S. (2007). Cytochrome P450 2B6 is a growth-inhibitory and prognostic factor for prostate cancer. Prostate 67(10), 1029-37.
