B.A., 1985, Genetics, University of California-Berkeley
Ph.D., 1991, Physiology, University of California-Berkeley
Postdoctoral research: UC-San Francisco and UC-San Diego
The focus of our research is on understanding the molecular mechanisms governing the activity of estrogen receptor (ER), a member of the nuclear receptor transcription factor family that is critical in normal reproduction and is implicated in the pathogenesis of breast cancer.
ER is an intracellular receptor that when activated by estrogen and other estrogen-like compounds, binds directly to DNA and activates or represses gene transcription. It serves as an important model for the understanding of basic mechanisms of transcription, as well as the regulatory pathways that control the cellular responses to steroid hormones.
Currently, we are pursuing projects that address the role of post-translational regulation in the control of ERa protein activity, with emphasis on proteasome-mediated proteolysis. Experiments are aimed at better defining the signals that target ER for destruction and understanding how protein stability affects ERa transcriptional function.
In trying to elucidate the link between protein stability and transactivation, our research has identified novel regulatory and activation mechanisms for ERa and is placed into an emerging model of a “transcriptional clock” (Figure 1) that explores the dynamics and specificity of macromolecular complexes governing gene expression.
Figure 1: Model of a "Transcriptional Clock"
Morgan MM, Johnson BP, Livingston MK, Schuler LA, Alarid ET, Sung KE, Beebe DJ. Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement. Pharmacol Ther. 2016 Sep;165:79-92. doi: 10.1016/j.pharmthera.2016.05.007. Epub 2016 May 21. Review. PubMed PMID: 27218886. PubMed Central PMCID: PMC5439438.
Regier MC, Alarid ET, Beebe DJ. Progress towards understanding heterotypic interactions in multi-culture models of breast cancer. Integr Biol (Camb). 2016 Jun 13;8(6):684-92. doi: 10.1039/c6ib00001k. Epub 2016 Apr 21. PubMed PMID: 27097801; PubMed Central PMCID: PMC4993016.
Regier MC, Maccoux LJ, Weinberger EM, Regehr KJ, Berry SM, Beebe DJ, Alarid ET. Transitions from mono- to co- to tri-culture uniquely affect gene expression in breast cancer, stromal, and immune compartments. Biomed Microdevices. 2016 Aug;18(4):70. doi: 10.1007/s10544-016-0083-x. PubMed PMID: 27432323. PubMed Central PMCID: PMC5076020
Helzer KT, Hooper C, Miyamoto S, Alarid ET. Ubiquitylation of nuclear receptors: new linkages and therapeutic implications. J Mol Endocrinol. 2015 Jun;54(3):R151-67. doi: 10.1530/JME-14-0308. Epub 2015 May 5. Review. PubMed PMID: 25943391; PubMed Central PMCID: PMC4457637.
Rajbhandari P, Ozers MS, Solodin NM, Warren CL, Alarid ET. Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α. J Biol Chem. 2015 May 29;290(22):13749-62. doi: 10.1074/jbc.M114.621698. Epub 2015 Apr 12. PubMed PMID: 25866209; PubMed Central PMCID: PMC4447953.
Tian D, Solodin NM, Rajbhandari P, Bjorklund K, Alarid ET, Kreeger PK. A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer. FASEB J. 2015 May;29(5):2022-31. doi: 10.1096/fj.14-265637. Epub 2015 Feb 3. PubMed PMID: 25648997; PubMed Central PMCID: PMC4415015.
Berry, S. M., Singh, C., Lang, J. D., Strotman, L. N., Alarid, E. T., and Beebe, D. J. Streamlining Gene Expression Analysis: Integration of Co-Culture and mRNA Purification. Integr. Biol., 6(2): 224-231, 2014.
Rajbhandari, P., Schalper, K. A., Solodin, N. M., Ellison-Zelski, S. J., Lu, K. P., Rimm, D. L., and Alarid, E. T. Pin1 Modulates ERα Levels in Breast Cancer through Inhibition of Phosphorylation-Dependent Ubiquitination and Degradation. Oncogene, 33(11): 1438-1447, 2014.
Lang, J. D., Berry, S. M., Powers, G. L., Beebe, D. J., and Alarid, E. T. Hormonally Responsive Breast Cancer Cells in a Microfluidic Co-Culture Model as a Sensor of Microenvironmental Activity. Integr. Biol. (Camb.), 5(5): 807-816, 2013.
Powers, G. L., Rajbhandari, P., Solodin, N. M., Bickford, B., and Alarid, E. T. The Proteasome Inhibitor Bortezomib Induces an Inhibitory Chromatin Environment at a Distal Enhancer of the Estrogen Receptor-α Gene. PLoS One, 8(12):e81110, 2013.
Rajbhandari, P., Finn, G., Solodin, N. M., Singarapu, K. K., Sahu, S. C., Markley, J. L., Kadunc, K. J., Ellison-Zelski, S. J., Kariagina, A., Haslam, S. Z., Lu, K. P., and Alarid, E. T. Regulation of Estrogen Receptor α N-Terminus Conformation and Function by Peptidyl Prolyl Isomerase Pin1. Mol. Cell. Biol., 32: 445-457, 2012.
Member, National Cancer Institute - Cancer Genetics (CG) and Cancer Fellowships (F30, F31, F32); ONC 1 - Basic Translational IRG, 2013
Member, Ford Foundation Dissertation and Post-doctoral Fellowships - Biological Sciences Panel, 2013-present
Member, Wellcome Trust Research Training Fellowship, United Kingdom, 2013
Member, UK Breast Cancer Campaign-Predoctoral review panel, 2013
Member, National Science Foundation Dissertation and Post-doctoral Fellowship - Molecular and Developmental Biology Review Panel, 2013