Dr Robert Clarke PhD

Photograph of Robert Clarke

Reader in Breast Biology

Breast Cancer Now Research Unit

Institute of Cancer Sciences

Manchester Cancer Research Centre

University of Manchester

Wilmslow Road

Manchester

M20 4QL

Role

Director (2015- ), Manchester Breast Centre, which comprises 21 basic, translational and clinician scientists active in breast cancer research:

http://www.breastcentre.manchester.ac.uk/

Former President (2012-2014) and Board Member, International Association for Breast Cancer Research

Editorial Board: American Journal of Pathology, Breast Cancer Research and Journal of Mammary Gland Biology and Neoplasia

Memberships of Committees and Professional Bodies

Service on committees

Organising committee for the 8th European Network for Breast Development and Cancer (ENBDC) Workshop, Luzern, Switzerland, May 12th-14th, 2016.

http://www.enbdc.org/

Organising Committee for 6th Annual ‘Targeting Notch in Cancer’ Conference, 15th - 17th June, 2016.

http://www.cancerconferences.org/annual_meetings/information-notch.html

Research

The goal of our research is to understand the hierarchical relationship between cells in breast epithelium in order to gain an insight into the processes that underlie cancer initiation in this tissue. The primary aim, therefore, is to characterise and to understand the regulation of mammary epithelial stem cells since these are likely to be the targets of cancer-initiating events, and may be the underlying tumourigenic cells in breast cancers. We also wish to understand how steroid hormones such as oestrogen regulate this cellular hierarchy since both normal and tumour development is hormone dependent.

Development of the mammary gland involves the formation of collecting ducts and lobules, both of which are bilayered epithelia made up of contractile myo-epithelial and milk-producing luminal cells. One current interest is which of the Notch, Wnt, TGFbeta, EGF pathways and other relevant (eg. cytokines, Prl, GH and ovarian hormones) signalling pathways regulate stem cell self-renewal. We are also exploiting gene expression arrays, methods for functional genomics and proteomics to identify novel pathways that participate in stem cell regulation.

Identification of stem cell self-renewal pathways may be important for future cancer prevention and therapy. An emerging concept is that in leukemia as well as in neural and epithelial cancers, including breast cancer, only a minority of cells, i.e. the “cancer stem cells”, have the capacity to initiate tumours. Characterising the cancer stem cell and understanding the molecular basis for dysregulated self-renewal is crucial for identification of a) targets for effective therapeutic intervention, and b) those cells in micrometastases which can initiate tumours.

A second theme in the lab is identifying early changes that occur in normal and premalignant tissues and predict the emergence of a tumour. If these changes can be detected and prevented, then it may be possible to reduce the increasing incidence of breast cancer, particularly in the developed Western countries where the lifetime risk of breast cancer now exceeds one in ten women.

The results of these investigations should lead to an increased understanding of the biology of the normal human breast which, in turn, could lead to the development of new strategies or new targets for breast cancer prevention and therapy.

Latest Publications:

Harvie MN, Sims AH, Pegington M, Spence K, Mitchell A, Vaughan AA, Allwood JW, Xu Y, Rattray NJW, Goodacre R, Evans DGR, Mitchell E, McMullen D, Clarke RB and Howell A (2016) Intermittent energy restriction induces changes in breast gene expression and systemic metabolism Breast Cancer Research, in press.

Yu L, Fan Z, Fang S, Yang J, Gao T, Simões BM, Eyre R, Guo W and Clarke RB (2016) Cisplatin Selects for Stem-like Cells in Osteosarcoma by Activating Notch Signaling, OncoTarget, Advanced Online, April 20.

Teaching

Lectures on Cancer Stem Cells in final year BSc Biology and MSc Oncology courses.

Biography

I did my undergraduate BSc studies in Biology at the University of Sussex and the Université de Grenoble.  Following two and half years as a Research Assistant with Professor Potten at the Paterson Institute for Cancer Research, I studied the control of proliferation in the normal and neoplastic human mammary gland for my PhD at The University of Manchester (1995). Subsequently, I undertook post-doctoral training with Dr Liz Anderson in the Clinical Research Department of The Christie, Manchester. I returned to The University of Manchester as a Cancer Research UK Research Fellow in 2001, becoming a Group Leader in the Division of Cancer Studies based at the Paterson Institute for Cancer Research.  I am currently a Reader in Breast Biology in the Breast Cancer Now Research Unit and Director of the Manchester Breast Centre at the Institute of Cancer Sciences, University of Manchester.

Qualifications

BSc (Hons), PhD

Collaborators and affiliated staff

Lab staff

  • Ahmet Ucar, PhD - Breast Cancer Now-funded Senior Postdoctoral Research Associate
  • Rachel Eyre, PhD - Breast Cancer Now-funded Postdoctoral Research Associate
  • Bruno Simões, PhD - Breast Cancer Now-funded Postdoctoral Research Associate
  • Denis Alférez, PhD - MRC P2D-funded Postdoctoral Research Associate
  • Angélica Santiago Gómez, PhD - Rosetrees Trust-funded Research Fellow
  • Kath Spence, BSc - Breast Cancer Now-funded Senior Scientific Officer
  • Aida Sarmiento Castro, BSc - MRC-funded PhD Student
  • Alice Greenalgh, BSc - BBSRC-funded PhD Student (co-supervised with Sacha Howell)
  • Vanessa Clay, MBChB (Hons) and MRCP - MCRC-funded Clinical Fellow and PhD Student (co-supervised with David Gilham)
  • Aoife Kilgallon, BSc - MRC-funded PhD Student (co-supervised with David Gilham)
  • Sarah Kitson, MBChB (Hons) and MRCP - Clinical Fellow and PhD Student (co-supervised with Emma Crosbie)
  • Simon Timbrell, MBChB (Hons) and MRCP - Royal College of Surgeon's-funded Clinical Fellow and PhD Student (co-supervised with Nigel Bundred)
  • Fen Tang, BMed, MBChB - British Council-Chinese Govt.-funded Visiting PhD Student (Jinan University, Guangzhou)
  • Elena Spina, BSc - Visiting PhD Student (University of Calabria, Italy)

Selected publications

2016

  • Clarke, R. B., Aires, A., Ocampo, S. M., Simões, B. M., Rodriguez, M. J., Couleaud, P., ... Cortajarena, A. L. (2016). Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44 positive cancer cells. Nanotechnology, 27(6), 065103.. Publication link: 9ffd9bbb-88fe-40fc-93e1-e50cdc4fe149
  • Clarke, R. B., Giordano, C., Chemi, F., Panza, S., Bonofiglio, I. B. D., Lanzino, M., ... Andò, S. (2016). Leptin as a Mediator of Tumor-Stromal Interactions Promotes Breast Cancer Stem Cell Activity. Oncotarget, 7(2), 1262-1275.. Publication link: 4b8d0538-3639-4abe-bafb-3b57a2a31c6c
  • Clarke, R. B., Smit, L., Berns, K., Spence, K., Ryder, W. D., Zeps, N., ... Bernards, R. (2016). An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation. Oncotarget, 7(3), 2596-2610.. Publication link: 74941b21-5ac0-447a-a02f-3b2bec62fe89

2015

  • Clarke, R. B., Simões, B. M., O’Brien, C. S., Eyre, R., Silva, A., Yu, L., ... Howell, S. J. (2015). Anti-estrogen resistance in human breast tumors is driven by JAG1-NOTCH4-dependent cancer stem cell activity. Cell Reports, 12(12), 1968-1977.. Publication link: 511e7e9e-8468-4f60-8829-0414d4034d4a
  • Clarke, R. B., Simões, B., Alferez, D., & Howell, S. (2015). The role of steroid hormones in breast cancer stem cells,. Endocrine - Related Cancer, 22 (6):T177-86(6), 177-186. [ERC-15-0350].. Publication link: 56b51916-f47e-4c64-9f03-b1d6f0633d97
  • Clarke, R. B., Williams, K. E., Bundred, N. J., Landberg, G., & Farnie, G. (2015). Focal Adhesion Kinase and Wnt Signaling Regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells (Durham), 33, 327-341.. Publication link: cbca6f0f-b7af-42a3-8c9a-2933347ab618

2014

  • Ablett, M. P., O'Brien, C. S., Sims, A. H., Farnie, G., & Clarke, R. B. (2014). A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. Oncotarget, 5(3), 599-612.. Publication link: b59b3556-de01-495a-908c-7c3afa50772d
  • Bundred, N. J., Farnie, G., Johnson, R. L., Williams, K. E., Clarke, R. B., Johnson, R. L., ... Clarke, R. B. (2014). Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS).Cell Cycle, 13(3), 418-425. 10.4161/cc.27201. Publication link: 3c8af09d-4164-422c-9230-be08e085c931 | DOI:10.4161/cc.27201
  • Clarke, R. B., Vieira, A. F., Ribeiro, A. S., Dionísio, M. R., Sousa, B., Nobre, R., ... Paredes, J. (2014). P-cadherin intracellular signalling is dependent on α6β4 integrin activation inducing stem cell and invasive properties in human breast cancer cells. Oncotarget, 5(3), 679-692.. Publication link: 5491a930-eee0-4866-bd3f-c1e4296e1242
  • Hidalgo, M., Amant, F., Biankin, A. V., Budinská, E., Byrne, A. T., Caldas, C., ... Villanueva, A. (2014). Patient-derived Xenograft models: An emerging platform for translational cancer research. Cancer Discovery, 4(9), 998-1013. 10.1158/2159-8290.CD-14-0001. Publication link: d27a02fb-05ab-4d7d-b256-205a3ff07c7d | DOI:10.1158/2159-8290.CD-14-0001
  • Lamb, R., Lisanti, M. P., Clarke, R. B., & Landberg, G. (2014). Co-ordination of cell cycle, migration and stem cell-like activity in breast cancer. Oncotarget, 5(17), 7833-7842.. Publication link: 6c524989-dc3e-4cc5-9bdb-330dc4a9576c

2013

  • Clarke, R. B., Harrison, H., Rogerson, L., Gregson, H. J., Brennan, K. R., & Landberg, G. (2013). Contrasting hypoxic effect on breast cancer stem cell hierarchy is dependent on ERα status. Cancer Research, 73(4), 1420-1433.. Publication link: 6c2a05e2-09f2-4438-92bb-f1395ed4037d
  • Clarke, R. B., Singh, J. K., Simões, B. M., Howell, S. J., & Farnie, G. (2013). Recent Advances Reveal IL-8 Signalling as a Potential Key to Targeting Breast Cancer Stem Cells. Breast Cancer Research, 15, 210.. Publication link: 831562ca-3eb3-4301-913c-f4833db3cb15
  • Lamb, R., Ablett, M. P., Spence, K., Landberg, G., Sims, A. H., & Clarke, R. B. (2013). Wnt Pathway Activity in Breast Cancer Sub-Types and Stem-Like Cells. PLoS ONE, 8(7), [e67811]. 10.1371/journal.pone.0067811. Publication link: 33a82c9e-0e42-4466-aef1-69543aa7495d | DOI:10.1371/journal.pone.0067811 | PubMed:23861811
  • Lamb, R., Lehn, S., Rogerson, L., Clarke, R. B., Landberg, G., & Hodgson, L. (2013). Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity.Cell cycle (Georgetown, Tex.), 12(15), 2384-2394. 10.4161/cc.25403. Publication link: 4b545cc4-4da6-40fc-9678-03bef05e7563 | DOI:10.4161/cc.25403 | PubMed:23839043
  • McClements, L., Yakkundi, A., Papaspyropoulos, A., Harrison, H., Ablett, M. P., Jithesh, P. V., ... Robson, T. (2013). Targeting treatment-resistant breast cancer stem cells with FKBPL and Its peptide derivative, AD-01, via the CD44 pathway. Clinical Cancer Research, 19(14), 3881-3893. 10.1158/1078-0432.CCR-13-0595. Publication link: 5300e7ab-78ff-4023-b08b-5e265f04d8d1 | DOI:10.1158/1078-0432.CCR-13-0595
  • Simoes, B., Harrison, H., Simões, B. M., Rogerson, L., Howell, S. J., Landberg, G., ... Landberg, G. (2013). Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Research, 15(2), [R21]. 10.1186/bcr3396. Publication link: b067ff7b-f20b-4058-8bdc-017bf10ae981 | DOI:10.1186/bcr3396 | PubMed:23497505
  • Singh, J. K., Farnie, G., Bundred, N. J., Simões, B. M., Shergill, A., Landberg, G., ... Clarke, R. B. (2013). Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms.Clinical cancer research : an official journal of the American Association for Cancer Research, 19(3), 643-656. 10.1158/1078-0432.CCR-12-1063. Publication link: ef655c4f-25fa-40eb-84d2-2c2755c681c9 | DOI:10.1158/1078-0432.CCR-12-1063 | PubMed:23149820

2012

  • Ablett, M. P., Singh, J. K., & Clarke, R. B. (2012). Stem cells in breast tumours: Are they ready for the clinic?. European Journal of Cancer, 48(14), 2104-2116. 10.1016/j.ejca.2012.03.019. Publication link: d67aa3c7-779d-4ff7-8b2d-7b9325e1f3cf | DOI:10.1016/j.ejca.2012.03.019
  • Shaw, F. L., Harrison, H., Spence, K., Ablett, M. P., Simoes, B. M., Farnie, G., & Clarke, R. B. (2012). A detailed mammosphere assay protocol for the quantification of breast stem cell activity. Journal of Mammary Gland Biology and Neoplasia, 17(2), 111-117. 10.1007/s10911-012-9255-3. Publication link: 551eb06c-bd73-41ea-a34b-77ec99cabfd4 | DOI:10.1007/s10911-012-9255-3 | PubMed:22665270
  • Vieira, A. F., Ricardo, S., Ablett, M. P., Dionísio, M. R., Mendes, N., Albergaria, A., ... Paredes, J. (2012). P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer. Stem Cells, 30(5), 854-864. 10.1002/stem.1075. Publication link: 938d2449-f580-48be-987d-0d261c54731d | DOI:10.1002/stem.1075

2011

  • Agur, Z., Kirnasovsky, O. U., Vasserman, G., Tencer-Hershkowicz, L., Kogan, Y., Harrison, H., ... Clarke, R. B. (2011). Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: An experimentally supported mathematical model. PLoS ONE, 6(9), [e24225]. 10.1371/journal.pone.0024225. Publication link: 9807c89b-8085-49b4-bf92-a5939e4066e7 | DOI:10.1371/journal.pone.0024225 | PubMed:21915302
  • Thompson, A. M., Johnson, A., Quinlan, P., Hillman, G., Fontecha, M., Bray, S. E., ... Newman, W. G. (2011). Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Research and Treatment, 125(1), 279-287. 10.1007/s10549-010-1139-x. Publication link: 8795234d-6ed3-4c11-add7-7c7516d321c0 | DOI:10.1007/s10549-010-1139-x | PubMed:20809362

2010

  • Harrison, H., Farnie, G., Howell, S. J., Rock, R. E., Stylianou, S., Brennan, K. R., ... Clarke, R. B. (2010). Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Research, 70(2), 709-718. 10.1158/0008-5472.CAN-09-1681. Publication link: f40c35c7-fd19-49d0-866d-a60927566d8a | DOI:10.1158/0008-5472.CAN-09-1681 | PubMed:20068161
  • Rieger, M. E., Sims, A. H., Coats, E. R., Clarke, R. B., & Briegel, K. J. (2010). The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers. Molecular and Cellular Biology, 30(17), 4267-4279. 10.1128/MCB.01418-09. Publication link: cc2d2b58-2947-4820-a9d2-40439b7494a4 | DOI:10.1128/MCB.01418-09

2009

  • Blance, R. N., Sims, A. H., Anderson, E., Howell, A., & Clarke, R. B. (2009). Normal breast tissue implanted into athymic nude mice identifies biomarkers of the effects of human pregnancy levels of estrogen. Cancer Prevention Research, 2(3), 257-264. 10.1158/1940-6207.CAPR-08-0161. Publication link: f175406f-cc13-49b6-a419-bf7984cbd9a9 | DOI:10.1158/1940-6207.CAPR-08-0161
  • Ong, K. R., Sims, A. H., Harvie, M., Chapman, M., Dunn, W. B., Broadhurst, D., ... Howell, A. (2009). Biomarkers of dietary energy restriction in women at increased risk of breast cancer. Cancer Prevention Research, 2(8), 720-731. 10.1158/1940-6207.CAPR-09-0008. Publication link: adb1ba0f-2d58-442b-8d6e-998276243b18 | DOI:10.1158/1940-6207.CAPR-09-0008 | PubMed:19656771

2008

  • Howell, S. J., Anderson, E., Hunter, T., Farnie, G., & Clarke, R. B. (2008). Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity.Breast cancer research : BCR, 10(4), [R68]. 10.1186/bcr2129. Publication link: c411c044-97a8-454d-946f-bb16ec499d26 | DOI:10.1186/bcr2129 | PubMed:18681966

2007

  • Farnie, G., Clarke, R. B., Spence, K., Pinnock, N., Brennan, K., Anderson, N. G., & Bundred, N. J. (2007). Novel cell culture technique for primary ductal carcinoma in situ: Role of notch and epidermal growth Factor Receptor Signaling Pathways. Journal of the National Cancer Institute, 99(8), 616-627. 10.1093/jnci/djk133. Publication link: 1b1f960e-416b-4062-9ace-0abd24fba57d | DOI:10.1093/jnci/djk133 | PubMed:17440163

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