Robert Clarke (academic)

Short description: Northern Irish oncology researcher

Robert Clarke

Nationality| Northern Irish
Occupation| Oncology researcher and academic administrator
Awards| Fellow, American Association for the Advancement of Science
Academic background
Education| B.S., Biological Sciences
M.S., Biochemistry
Ph.D., Biochemistry
D.Sc., Biochemistry
Alma mater| Ulster University
Queen's University Belfast
Academic work
Institutions| The Hormel Institute, University of Minnesota
Georgetown University

Robert Clarke is a Northern Irish oncology researcher and academic administrator. He is the executive director of The Hormel Institute, a professor of biochemistry, Molecular Biology and Biophysics at the University of Minnesota,[1] and ab Adjunct Professor of Oncology at Georgetown University.

With his work focused in breast cancer research, Clarke studies how hormones (endogenous and exogenous) and related factors affect breast cancer. He has authored over 340 publications,[2] and has 5 patents awarded. His research primarily focuses on determining an individual patient’s prognosis and the likelihood that they will respond to specific systemic therapies. His laboratory also studies drug resistance and the role of cell-cell communication in affecting dormancy and responsiveness to endocrine therapies breast cancers that express the estrogen receptor.[3]

Clarke is an elected Fellow of American Association for the Advancement of Science,[4] the Royal Society of Chemistry, the Royal Society of Medicine, and the Royal Society of Biology. He is a Senior Editor for the journal Cancer Research.[5]

## Contents

* 1 Education
* 2 Career
* 3 Research
* 3.1 Breast cancer
* 3.2 Aspects of Acquired Endocrine Resistance in Breast Cancer
* 4 Awards and honors
* 5 Bibliography
* 6 References

## Education

Clarke studied at the University of Ulster, and received his bachelor's degree in biological sciences in 1980. He then enrolled at Queen’s University of Belfast, and earned a M.Sc. in 1982, a Ph.D. in 1986, and a D.Sc. in 1999 (each in biochemistry). He completed his postdoctoral training at the Medical Breast Section of the National Cancer Institute in 1988.[1]

## Career

Following his postdoctoral training, Clarke joined Georgetown University School of Medicine as an assistant professor of physiology and biophysics, and was promoted to associate professor of oncology in 1995, and to professor in 1999. In 2020, he held an appointment at Georgetown University as an adjunct professor of oncology.[1]

Clarke also held several administrative appointments in his career. He served as secretary/treasurer of the Georgetown University Senate from 2004 till 2007, as associate vice president of GUMC and director of Biomedical Graduate Research Organization from 2007 till 2019, as co-leader of Breast Cancer Program 2006 till 2020, and as dean for research 2011 till 2019 at Georgetown University. Since 2020 he serves as executive director of The Hormel Institute, University of Minnesota.[6]

## Research

Clarke's work is focused on how hormones (endogenous and exogenous) and related factors affect breast cancer. He initially focused on the interactions of hormones and anticancer drugs, and then expanded the work into studies of the underlying cellular and molecular mechanisms that explain how breast cancers become resistant to hormone and cytotoxic therapies. He and his colleagues have developed a series of hormone resistant breast cancer models that are now used in the field.[7][8][9]

### Breast cancer

Clarke’s research team and collaborators discovered a new signaling network and control mechanism that contributes to the hormonal regulation of breast cancer cell proliferation and cell death in response to estrogens,[10][11] aromatase inhibitors, and antiestrogens[12] This signaling includes communication between the endoplasmic reticulum and mitochondria, and reflects novel interactions within the unfolded protein response. His group has also identified interferon regulatory factor-1 as a breast cancer suppressor gene,[13][14] and worked on the development and application of genomic and novel bioinformatic methods in translational breast cancer studies [15][16]

### Aspects of Acquired Endocrine Resistance in Breast Cancer

Clarke identified some of the first non-nuclear activities of endocrine therapies including the effects of Tamoxifen and high dose estrogens on membrane fluidity.[17] In his studies regarding drug resistance and MDR1/P-glycoprotein,[18] he published the first statistical meta-analysis of the role of MDR1 in breast cancer,[19] and defined novel mechanisms of resistance to Taxanes.[20][21] He was among the pioneers to implicate the unfolded protein response (UPR) in acquired endocrine resistance[11][22] and in regulating involution in the normal mammary gland.[23] In addition, his research team was among the first to implicate key BCL2 family members, interferon regulatory factor-1 and NFκB in the endocrine resistant phenotype,[22] and to define basic interactions among the UPR, autophagy and apoptosis,[24] regulation of immune markers,[25] and the role for epigenetic changes in terms of determining trans-generational effects on endocrine responsiveness.[26]

In his studies on the endocrine-mediated regulation of breast cancer progression and cell fate, he explored the concept that the final cell-fate decision is based on integrated signaling that flows through the endoplasmic reticulum, mitochondria and nucleus. Together, this signaling is represented in a modular network that regulates and executes five key cell function modules (autophagy, cell death, metabolism, proliferation, and UPR).[10][11][27]

## Awards and honors

* 2012 - Sigma Xi Distinguished Lecturer, National Cancer Institute[28]
* 2019 - Fellow, the American Association for the Advancement of Science[4]

## Bibliography

* Clarke, R., Brünner, N., Katzenellenbogen, B.S., Thompson E.W., Norman, M.J., Koppi, C., Paik, S., Lippman, M.E. & Dickson, R.B. (1989). Progression from hormone dependent to hormone independent growth in MCF-7 human breast cancer cells. Proceedings of the National Academy of Sciences USA, 86(10), 3649–3653.
* Trock, B. J., Leonessa, F., & Clarke, R. (1997). Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. Journal of the National Cancer Institute, 89(13), 917–931.
* Trock, B. J., Hilakivi-Clarke, L., & Clarke, R. (2006). Meta-analysis of soy intake and breast cancer risk. Journal of the National Cancer Institute, 98(7), 459–471.
* Clarke, R., Ressom, H. W., Wang, A., Xuan, J., Liu, M. C., Gehan, E. A., & Wang, Y. (2008). The properties of high-dimensional data spaces: implications for exploring gene and protein expression data. Nature Reviews Cancer, 8(1), 37–49.
* Tyson, J.J., Baumann, W.T., Chen, C., Verdugo, A., Tavassoly, I., Wang, Y., Weiner, L.M. & Clarke, R. (2011). Dynamic modelling of estrogen signaling and cell fate in breast cancer cells. Nature Reviews Cancer, 11(7): 523–532.

## References

1. ↑ 1.0 1.1 1.2 "Robert Clarke, Ph.D., D.Sc.". https://www.hi.umn.edu/portfolio-items/robert-clarke/.
2. ↑ "Robert Clarke". https://scholar.google.com/citations?user=BgsjeHMAAAAJ&hl=en.
3. ↑ Clarke, Robert; Tyson, John J.; Dixon, J. Michael (December 15, 2015). "Endocrine resistance in breast cancer – an overview and update". Molecular and Cellular Endocrinology 418 (3): 220–234. doi:10.1016/j.mce.2015.09.035. PMID 26455641.
4. ↑ 4.0 4.1 "AAAS Announces Leading Scientists Elected as 2019 Fellows | American Association for the Advancement of Science". https://www.aaas.org/news/aaas-announces-leading-scientists-elected-2019-fellows.
5. ↑ "Editorial Board | Cancer Research". https://cancerres.aacrjournals.org/edboard.
6. ↑ "Robert Clarke, Ph.D., D.Sc.". https://www.hi.umn.edu/portfolio-items/robert-clarke/.
7. ↑ Brünner, N.; Boulay, V.; Fojo, A.; Freter, C. E.; Lippman, M. E.; Clarke, R. (January 15, 1993). "Acquisition of hormone-independent growth in MCF-7 cells is accompanied by increased expression of estrogen-regulated genes but without detectable DNA amplifications". Cancer Research 53 (2): 283–290. PMID 8380254. https://pubmed.ncbi.nlm.nih.gov/8380254/.
8. ↑ Brünner, N.; Frandsen, T. L.; Holst-Hansen, C.; Bei, M.; Thompson, E. W.; Wakeling, A. E.; Lippman, M. E.; Clarke, R. (July 15, 1993). "MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780". Cancer Research 53 (14): 3229–3232. PMID 8324732. https://pubmed.ncbi.nlm.nih.gov/8324732/.
9. ↑ Brünner, N.; Boysen, B.; Jirus, S.; Skaar, T. C.; Holst-Hansen, C.; Lippman, J.; Frandsen, T.; Spang-Thomsen, M. et al. (August 15, 1997). "MCF7/LCC9: an antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen". Cancer Research 57 (16): 3486–3493. PMID 9270017. https://pubmed.ncbi.nlm.nih.gov/9270017/.
10. ↑ 10.0 10.1 Tyson, John J.; Baumann, William T.; Chen, Chun; Verdugo, Anael; Tavassoly, Iman; Wang, Yue; Weiner, Louis M.; Clarke, Robert (July 10, 2011). "Dynamic modelling of oestrogen signalling and cell fate in breast cancer cells". Nature Reviews Cancer 11 (7): 523–532. doi:10.1038/nrc3081. PMID 21677677.
11. ↑ 11.0 11.1 11.2 Clarke, Robert; Cook, Katherine L.; Hu, Rong; Facey, Caroline O. B.; Tavassoly, Iman; Schwartz, Jessica L.; Baumann, William T.; Tyson, John J. et al. (March 15, 2012). "Endoplasmic Reticulum Stress, the Unfolded Protein Response, Autophagy, and the Integrated Regulation of Breast Cancer Cell Fate". Cancer Research 72 (6): 1321–1331. doi:10.1158/0008-5472.CAN-11-3213. PMID 22422988. PMC 3313080. https://cancerres.aacrjournals.org/content/72/6/1321.short.
12. ↑ Wang, Li Hua; Yang, Xiao Yi; Zhang, Xiaohu; An, Ping; Kim, Han-Jong; Huang, Jiaqiang; Clarke, Robert; Osborne, C. Kent et al. (December 10, 2006). "Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer". Cancer Cell 10 (6): 487–499. doi:10.1016/j.ccr.2006.09.015. PMID 17157789.
13. ↑ Bouker, Kerrie B.; Skaar, Todd C.; Riggins, Rebecca B.; Harburger, David S.; Fernandez, David R.; Zwart, Alan; Wang, Antai; Clarke, Robert (September 10, 2005). "Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis". Carcinogenesis 26 (9): 1527–1535. doi:10.1093/carcin/bgi113. PMID 15878912.
14. ↑ Bouker, Kerrie B.; Skaar, Todd C.; Harburger, David S.; Riggins, Rebecca B.; Fernandez, David R.; Zwart, Alan; Clarke, Robert (May 10, 2007). "The A4396G polymorphism in interferon regulatory factor 1 is frequently expressed in breast cancer cell lines". Cancer Genetics and Cytogenetics 175 (1): 61–64. doi:10.1016/j.cancergencyto.2006.12.008. PMID 17498560. https://pubmed.ncbi.nlm.nih.gov/17498560/.
15. ↑ Clarke, Robert; Ressom, Habtom W.; Wang, Antai; Xuan, Jianhua; Liu, Minetta C.; Gehan, Edmund A.; Wang, Yue (January 10, 2008). "The properties of high-dimensional data spaces: implications for exploring gene and protein expression data". Nature Reviews Cancer 8 (1): 37–49. doi:10.1038/nrc2294. PMID 18097463.
16. ↑ Fan, Ming; Xia, Pingping; Clarke, Robert; Wang, Yue; Li, Lihua (September 25, 2020). "Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer". Nature Communications 11 (1): 4861. doi:10.1038/s41467-020-18703-2. PMID 32978398. Bibcode: 2020NatCo..11.4861F.
17. ↑ Clarke, R.; van den Berg, H. W.; Murphy, R. F. (November 7, 1990). "Reduction of the membrane fluidity of human breast cancer cells by tamoxifen and 17 beta-estradiol". Journal of the National Cancer Institute 82 (21): 1702–1705. doi:10.1093/jnci/82.21.1702. PMID 2231758. https://pubmed.ncbi.nlm.nih.gov/2231758/.
18. ↑ Clarke, R.; Currier, S.; Kaplan, O.; Lovelace, E.; Boulay, V.; Gottesman, M. M.; Dickson, R. B. (October 7, 1992). "Effect of P-glycoprotein expression on sensitivity to hormones in MCF-7 human breast cancer cells". Journal of the National Cancer Institute 84 (19): 1506–1512. doi:10.1093/jnci/84.19.1506. PMID 1359153. https://pubmed.ncbi.nlm.nih.gov/1359153/.
19. ↑ Trock, B. J.; Leonessa, F.; Clarke, R. (July 2, 1997). "Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance". Journal of the National Cancer Institute 89 (13): 917–931. doi:10.1093/jnci/89.13.917. PMID 9214671.
20. ↑ Shajahan, Ayesha N.; Wang, Aifen; Decker, Markus; Minshall, Richard D.; Liu, Minetta C.; Clarke, Robert (February 23, 2007). "Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity". Journal of Biological Chemistry 282 (8): 5934–5943. doi:10.1074/jbc.M608857200. PMID 17190831.
21. ↑ Shajahan, Ayesha N.; Dobbin, Zachary C.; Hickman, F. Edward; Dakshanamurthy, Sivanesan; Clarke, Robert (May 18, 2012). "Tyrosine-phosphorylated Caveolin-1 (Tyr-14) Increases Sensitivity to Paclitaxel by Inhibiting BCL2 and BCLxL Proteins via c-Jun N-terminal Kinase (JNK)". The Journal of Biological Chemistry 287 (21): 17682–17692. doi:10.1074/jbc.M111.304022. PMID 22433870.
22. ↑ 22.0 22.1 Z, Gu; Ry, Lee; Tc, Skaar; Kb, Bouker; Jn, Welch; J, Lu; A, Liu; Y, Zhu et al. (June 15, 2002). "Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780)". Cancer Research 62 (12): 3428–3437. PMID 12067985. https://pubmed.ncbi.nlm.nih.gov/12067985/.
23. ↑ Wärri, Anni; Cook, Katherine L.; Hu, Rong; Jin, Lu; Zwart, Alan; Soto-Pantoja, David R.; Liu, Jie; Finkel, Toren et al. (October 15, 2018). "Autophagy and unfolded protein response (UPR) regulate mammary gland involution by restraining apoptosis-driven irreversible changes". Cell Death Discovery 4 (1): 40. doi:10.1038/s41420-018-0105-y. PMID 30345078.
24. ↑ Cook, Katherine L.; Shajahan, Ayesha N.; Wärri, Anni; Jin, Lu; Hilakivi-Clarke, Leena A.; Clarke, Robert (July 1, 2012). "Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness". Cancer Research 72 (13): 3337–3349. doi:10.1158/0008-5472.CAN-12-0269. PMID 22752300.
25. ↑ Cook, Katherine L.; Soto-Pantoja, David R.; Clarke, Pamela A. G.; Cruz, M. Idalia; Zwart, Alan; Wärri, Anni; Hilakivi-Clarke, Leena; Roberts, David D. et al. (October 1, 2016). "Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer". Cancer Research 76 (19): 5657–5670. doi:10.1158/0008-5472.CAN-15-2616. PMID 27698188.
26. ↑ Hilakivi-Clarke, Leena; Wärri, Anni; Bouker, Kerrie B; Zhang, Xiyuan; Cook, Katherine L; Jin, Lu; Zwart, Alan; Nguyen, Nguyen et al. (September 8, 2016). "Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model". JNCI Journal of the National Cancer Institute 109 (1): djw188. doi:10.1093/jnci/djw188. PMID 27609189.
27. ↑ Clarke, Robert; Kraikivski, Pavel; Jones, Brandon C.; Sevigny, Catherine M.; Sengupta, Surojeet; Wang, Yue (September 10, 2020). "A systems biology approach to discovering pathway signaling dysregulation in metastasis". Cancer and Metastasis Reviews 39 (3): 903–918. doi:10.1007/s10555-020-09921-7. PMID 32776157.
28. ↑ "2012-2013". https://www.sigmaxi.org/programs/lectureships/past-lecturers/2012-2013.

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