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BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE Richard Baer Professor of Pathology & Cell Biology eRA COMMONS USER NAME (credential, e.g., agency login) BAERRJ EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) B.A. 1976 Biological Sciences Ph.D. 1981 Microbiology Rutgers College, New Brunswick, New Jersey Rutgers University, New Brunswick, New Jersey FIELD OF STUDY A. Personal Statement I am a Professor of Pathology & Cell Biology at Columbia University Medical Center (CUMC), the Deputy Director of the CUMC Institute for Cancer Genetics, and the Associate Director for Basic Science of the CUMC Herbert Irving Comprehensive Cancer Center. Since 1987, I have maintained an independent program of cancer research that has been supported continuously by R01/P01 grants from the NCI. My independent work was initially focused on the discovery and characterization of TAL1 and TAL2, proto-oncogenes that are malignantly activated in approximately half of patients with T cell acute lymphoblastic leukemia. For the past 20 years, I have studied the role of the BRCA1 tumor suppressor in hereditary breast cancer and genome stability. With regards to my training experience, I have served on the dissertation committees of over 55 successful Ph.D. candidates, including 12 of my own students, and mentored 22 postdoctoral fellows who are now pursuing productive careers in biomedical research within academic and industrial settings. Since 2005, I have also acted as Director of the NCI-sponsored (T32-CA009503) Cancer Biology Training Program for preand postdoctoral trainees in the cancer research laboratories of Columbia University. B. Positions, Honors, and Advisory Committees Positions 1981 - 1987: 1987 - 1990: 1990 - 1995: 1995 - 1999: 1999 - present: 2005 - present: 2007 - present: Postdoctoral Fellow; MRC-Laboratory of Molecular Biology, Cambridge, UK Assistant Professor of Microbiology; U.T. Southwestern Medical Center Associate Professor of Microbiology; U.T. Southwestern Medical Center Professor of Microbiology; U.T. Southwestern Medical Center, Dallas, TX Professor of Pathology & Cell Biology; Columbia University Medical Center (CUMC) Assoc. Director for Basic Science; CUMC Herbert Irving Comprehensive Cancer Center Deputy Director; CUMC Institute for Cancer Genetics Honors 1981 - 1982: 1983 - 1985: 1990 - 1992: 1993 - 1997: Postdoctoral Fellowship; Damon Runyon/Walter Winchell Cancer Fund Postdoctoral Fellowship; Lady Tata Memorial Trust Junior Faculty Research Award; American Cancer Society Faculty Research Award; American Cancer Society Advisory Committees 1991 - 1993: Ad Hoc; NIH - Pathology B Study Section 1993 - 1996: Member; NIH - Pathology B Study Section 2003 - 2004: Member; DoD Breast Cancer - Molecular Biology and Genetics review panel 2012 - present: Ad Hoc; NIH - Tumor Cell Biology Study Section 2015 – present: Ad Hoc; Komen Breast Cancer Foundation Review Committee C. Contributions to Science 1. Tumor-associated mutations of the c-Myc proto-oncogene in Burkitts’ lymphoma As a postdoctoral scientist in the laboratory of Dr. Frederick Sanger at the MRC Laboratory of Molecular Biology (Cambridge, UK) I collaborated with Dr. Terrence Rabbitts in the discovery of tumor-associated mutations in the translocated alleles of the c-Myc proto-oncogene in Burkitt’s lymphoma. At that time, the c-Myc translocations had been recently identified, but the mechanisms by which these translocations activate the malignant potential of c-Myc were not understood. Our findings uncovered two novel mechanisms of c-Myc activation: 1) mutation of transcriptional control sequences leading to deregulated c-Myc expression and 2) mutation of coding sequences leading to production of an altered c-Myc protein product. These results also revealed that juxtaposition of an oncogene adjacent to the immunoglobulin heavy chain locus renders it susceptible to somatic mutation in a manner analogous to recombined immunoglobulin variable gene segments. Interestingly, the coding mutations were clustered in a highly conserved region of c-Myc harboring two potential phosphorylation sites (T58 and S62). Although the concept of ubiquitin-mediated protein turnover had not yet been defined in the early 1980s, subsequent studies have shown that these mutations disrupt phospho-dependent control of c-Myc protein stability, providing a biochemical explanation for the malignant activation of c-Myc by chromosomal translocation. Rabbitts, T.H., Hamlyn, P.H., and Baer, R. (1983) Altered nucleotide sequence of a translocated c-myc gene in Burkitt's lymphoma. Nature 306: 760-765. Rabbitts, T.H., Forster, A., Hamlyn, P., and Baer, R. (1984) Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma. Nature 309: 592-597. 2. Molecular cloning of chromosome translocations associated with human T cell tumors After Dr. Sanger’s retirement in 1983, I continued my postdoctoral studies at the MRC in the laboratory of Dr. Terrence Rabbitts. Around that time, the T cell receptors that mediate immune recognition by T lymphocytes had been recently discovered. Since tumor-associated chromosome translocations of B cell malignancies often involve aberrant rearrangements of the immunoglobulin genes, we reasoned that the chromosome translocations of T cell malignancies would similarly feature rearrangements of the T cell receptor genes. Therefore, we cloned the T cell receptor / chain locus from human cells and used it to isolate and characterize the junctions of chromosomal translocation observed in human T cell lymphomas and leukemias. Baer, R., Chen, K.C., Smith, S., and Rabbitts, T.H. (1985) Fusion of an immunoglobulin variable gene and a T-cell receptor constant gene in the chromosome 14 inversion associated with T-cell tumors. Cell 43: 705-713. Baer, R., Forster, A., and Rabbitts, T.H. (1987) The mechanism of chromosome 14 inversion in a human T cell lymphoma. Cell 50: 97-105. Baer, R., Heppell, A., Taylor, A.M.R., Rabbitts, P.H., Boullier, B., and Rabbitts, T.H. (1987) The breakpoint of an inversion chromosome 14 in a T cell leukaemia; sequences downstream of the immunoglobulin heavy chain locus implicated in tumorigenesis. Proc. Natl. Acad. Sci. USA 84: 90699073. Baer, R., Boehm, T., Yssel, H., Spits, H., and Rabbitts, T.H. (1988) Complex rearrangements within the human J-C/J-C locus and aberrant recombination between J segments. EMBO J. 7: 1661-1668. 3. Discovery and characterization of the TAL1 and TAL2 proto-oncogenes In 1987, as an Assistant Professor at UT Southwestern Medical Center in Dallas, I set out to identify the molecular lesions responsible for T cell acute lymphoblastic leukemia (T-ALL). In the course of this work, we discovered two proto-oncogenes (TAL1 and TAL2) that are malignantly activated by chromosomal translocations. Indeed, we found that tumor-specific activation of TAL1, either by chromosomal rearrangement or ectopic expression, occurs in over 50% of T-ALL patients, establishing TAL1 activation as the most common genetic lesion associated with this disease. In total, we published over 25 papers describing the mechanisms of TAL1/2 activation in human T-ALL, as well as the functional and biochemical properties of their protein products. Chen, Q., Cheng, J.-T., Tsai, L.-H., Schneider, N., Buchanan, G., Carroll, A., Crist, W., Ozanne, B., Siciliano, M.J., and Baer, R. (1990) The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. EMBO J. 9: 415-424. Xia, Y., Brown, L., Yang, C.Y.-C., Tsan, J.T., Siciliano, M.J., Espinosa III, R., Le Beau, M.M. and Baer, R. (1991) TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T cell leukemia. Proc. Natl. Acad. Sci. USA 88: 11416-11420. Wadman, I., Li, J., Bash, R.O., Forster, A., Osada, H., Rabbitts, T.H., and Baer, R. (1994) Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. EMBO J. 13: 4831-4839. Bash, R.O., Hall, S., Timmons, C.F., Crist, W.M., Amylon, M., Smith, R.G., and Baer, R. (1995) Does activation of the TAL1 gene occur in a majority of patients with T cell acute lymphoblastic leukemia? A Pediatric Oncology Group Study. Blood 86: 666-676. 4. Discovery and characterization of the BRCA1/BARD1 heterodimer When the BRCA1 breast and ovarian cancer susceptibility gene was cloned in 1994, my laboratory set out to investigate its biological functions and elucidate the mechanisms by which it suppresses tumor development. Initially, we discovered the BARD1 protein and showed that it exists in vivo as a heterodimer with BRCA1. We further found that the biochemical, developmental, and tumor suppression functions of BRCA1 are mediated primarily, if not exclusively, by the BRCA1/BARD1 heterodimer. Through mammaryspecific inactivation of the Brca1 or Bard1 genes, we next developed mouse models of hereditary breast cancer that faithfully recapitulate the basal-like breast cancers that arise in women who carry germline BRCA1 mutations. We then used these models to define specific properties of BRCA1 that are (e.g., BRCT phospho-recognition) and are not (E3 ligase activity) required for tumor suppression. Wu, L.C., Wang, Z.W., Tsan, J.T., Spillman, M.A., Phung, A., Xu, X.L., Yang, M.-C.W., Hwang, L.-Y., Bowcock, A.M., and Baer, R. (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genetics 14: 430-440. Laufer, M., Nandula, S.V., Modi, A.P., Wang, S., Jasin, M., Murty, V.V., Ludwig, T., and Baer, R. (2007) Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homologydirected DNA repair. J. Biol. Chem. 282: 34325-34333. N/A Shakya, R., Szabolcs, M., McCarthy, E.E., Ospina, E., Basso, K., Nandula, S.V., Murty, V.V., Baer, R., and Ludwig, T. (2008) A common basal-like phenotype for mammary carcinomas induced by conditional inactivation of the BARD1 and BRCA1 tumor suppressors. Proc. Natl. Acad. Sci. USA 105: 7040-7045. PMCID: PMC236556593. Shakya, R., Reid, L.J., Reczek, C.R., Cole, F., Egli, D., Lin, C.-S., deRooij, D.G., Hirsch, S., Ravi, K., Hicks, J.B., Szabolcs, M., Jasin, M., Baer, R., and Ludwig, T. (2011) BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334: 525-528. PMCID: PMC2365565 5. Discovery and characterization of CtIP as a protein partner of BRCA1 Substantial evidence, including results from our Brca1 mouse breast cancer model, indicate that the carboxy-terminal (BRCT) domains of BRCA1 are essential for its tumor suppression activity. To ascertain the mechanism of tumor suppression, we sought to identify factors that associate with these domains in vivo. In the course of this work, we identified CtIP as a major interacting partner of BRCA1 and, in collaborative studies, demonstrated the requirements for CtIP in DNA resection, homology-directed repair of DNA double-strand breaks, and cell cycle checkpoint control. Yu, X., Wu, L.C., Bowcock, A.M., Aronheim, A., and Baer, R. (1998) The carboxy-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273: 25388-25392. N/A. Yu, X. and Baer, R. (2000) Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J. Biol. Chem. 275: 18541-18549. N/A. Sartori, A.A., Lukas, C., Coates, J., Fu, S., Baer, R., Lukas, J., and Jackson, S.P. (2007) CtIP cooperates with the MRE11 complex to promote DNA end resection. Nature 450: 509-514. PMCID: PMC2409435 Reczek, C.R., Szabolcs, M., Stark, J.M., Ludwig, T., and Baer, R. (2013) The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J. Cell Biol. 201: 693–707. PMCID: PMC3664708 D. Research Support (current) 1. NIH/NCI (1R01-CA172272-03). Principal Investigator: Richard Baer “The BARD1 tumor suppressor and breast cancer” July 1, 2013 – April 30, 2018 The aims of this proposal are to determine 1) how tumor-associated BARD1 mutations affect functions of the BRCA1/BARD1 heterodimer and 2) whether BRCT phosphoprotein recognition is required for the tumor suppression activity of BARD1. 2. NIH/NCI (5P01-CA097403-10). Principal Investigator: Richard Baer “Molecular Pathogenesis of Basal-like Breast Cancer” Project 3. Project Leader: Richard Baer “The Role of BRCA1/BARD1 in Basal-like Breast Cancer” September 1, 2009 – August 31, 2015 The Aims of Project 3 are 1) to determine whether the E3 ligase activity of BRCA1/BARD1 is required for normal development and BRCA1-mediated tumor suppression; 2) to determine whether the E3 ligase activity of BRCA1/BARD1 is required for DSB repair and cell cycle checkpoint control; 3) to dissect mechanisms of ubiquitin-mediated signaling by BRCA1/BARD1; and 4) examine interactions between the BRCA1 and PTEN pathways in the development of basal-like breast cancer. 3. NIH/NCI (1P01CA174653-02). Principal Investigator: Jean Gautier “DNA double-strand break repair, chromosomes translocations and cancer” Project 3. Project Leader: Richard Baer “The role of CtIP in Breast Carcinogenesis” April 8, 2014 – March 31, 2019 The Aims of Project 4 are to determine 1) how CtIP facilitates breast cancer development, 2) whether CtIP is required for development of basal-like breast cancer, and 3) whether Ctip is involved in Mycdriven breast cancer. 4. NIH/NCI (T32-CA09503-28). Principal Investigator: Richard Baer “Cancer Biology Training Program” September 1, 2012 – August 31, 2017 This grant is for a training program in cancer research that annually supports 4 predoctoral students and 4 postdoctoral fellows in laboratories at Columbia University. Dr. Baer’s role is Director of the Cancer Biology Training Program. 5. NIH/NCI (5P30-CA013696-39). Principal Investigator: Stephen Emerson “Cancer Center Support Grant” July 1, 2014 – June 30, 2019 This grant supports the NIH-designated Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University. The HICCC is responsible for the laboratory, clinical, and population-based cancer research programs and shared resources serving Cancer Center members at Columbia University Medical Center. Dr. Baer’s role is Associate Director for Basic Science.