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Dr Rob Clarke

Rob Clarke is dissecting human breast stem cell biology, using primary epithelium from both normal and malignant tissues. Rob’s interest is investigating the signalling pathways that differentially regulate stem cell self-renewal in normal versus cancer stem cells. An additional research area is the discovery of novel markers that can be used to isolate and purify these stem cell populations.

Reader in Breast Biology

Breast Biology Group
Manchester Cancer Research Centre
University of Manchester
Wilmslow Road
Manchester
M20 4QL
UK

Email: robert.clarke@manchester.ac.uk
Tel: +44 (0)161 306 0802

My undergraduate BSc studies in Biology were 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.

In 2001, I returned to The University of Manchester as a Cancer Research UK Research Fellow 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 Division of Cancer Sciences, University of Manchester.

Editorial work

Associate Editor:

American Journal of Pathology, 2008-2014

Breast Cancer Research, 2005-2014

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

Service on committees

Director of the Manchester Breast Centre, which comprises 27 basic, translational and clinician scientists active in breast cancer research:

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

Founder Member and Treasurer, European Network for Breast Development and Cancer (ENBDC):

http://www.enbdc.org/

Founder Member, EurOPDX Consortium:

http://europdx.eu/

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

Breast Cancer Now Catalyst Grants Committee (Europe), 2016-

Organising committee for the 2nd EurOPDX Workshop on Patient-derived Models of Cancer, Luzern, Switzerland, October 1st-3rd, 2018.

http://europdx.eu/news-events.html

Organising committee for the 11th European Network for Breast Development and Cancer (ENBDC) Workshop, Luzern, Switzerland, May 16th-18th 2019.

http://www.enbdc.org/

Organising Committee for 9th Annual ‘Targeting Notch in Cancer’ Conference, June 26th -28th, 2019.

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

Ethnicity influences breast cancer stem cells' drug resistance

Kamal, M., Nafie, E. H. O., Elsers, S., Alanwar, S., Ibrahim, R., Farag, F., Mlees, M., Simões, B. M., Spence, K., Santiago-Gómez, A., Salem, M. L. & Clarke, R. B. Jul 2018 In : Breast Journal. 24, 4, p. 701-703 3 p.

Research output: Contribution to journal › Article DOI: 10.1111/tbj.13021  Published

 

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Piggott, L., Silva, A., Robinson, T., Santiago-Gómez, A., Simões, B. M., Becker, M., Fichtner, I., Andera, L., Young, P., Morris, C., Barrett-Lee, P., Alchami, F., Piva, M., Vivanco, M. DM., Clarke, R. B., Gee, J. & Clarkson, R. 15 May 2018 In : Clinical Cancer Research. 24, 10, p. 2452-2463 12 p.

Research output: Contribution to journal › Article DOI: 10.1158/1078-0432.CCR-17-1381  Published

 

Estrogenicity of essential oils is not required to relieve symptoms of urogenital atrophy in breast cancer survivors

M Simoes, B., Kholer, B., Clarke, R., Stringer, J., Novak Frazer, L., Young, K., Richardson, R., Zucchini, G., Armstrong, A. & Howell, S. 2018 In : Therapeutic Advances in Medical Oncology. 10

Research output: Contribution to journal › Article DOI: 10.1177/1758835918766189  Published

 

GPER mediates the angiocrine actions induced by IGF1 through the HIF-1a/VEGF pathway in the breast tumor microenvironment

De Francesco, E., Sims, A. H., Maggiolini, M., Sotgia, F., Lisanti, M. P. & Clarke, R. 6 Dec 2017 In : Breast Cancer Research. 19, 1, p. 129 14 p.

Research output: Contribution to journal › Article  DOI: 10.1186/s13058-017-0923-5  Published

 

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Byrne, A. T. , Alférez, D. G. , Amant, F. , Annibali, D. , Arribas, J. , Biankin, A. V. , Bruna, A. , Budinská, E. , Caldas, C. , Chang, D. K. , Clarke, R. B. , Clevers, H. , Coukos, G. , Dangles-Marie, V. , Eckhardt, S. G. , Gonzalez-Suarez, E. , Hermans, E. , Hidalgo, M. , Jarzabek, M. A. , de Jong, S. & 22 others 2017 In : Nature reviews. Cancer.

Research output: Contribution to journal › Comment/debate DOI: 10.1038/nrc.2016.140

 

Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.

Giordano, C., Chemi, F., Panza, S., Bonofiglio, D., Lanzino, M., Cordella, A., Campana, A., Hashim, A., Rizza, P., Gyorffy, B., Simões, B. M., Clarke, R., Weisz, A., Catalano, S. & Andò, S.

Oncotarget. 2016. 7, 2, p. 1262-1275 13 p.

 

An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation

Smit, L., Berns, K., Spence, K., Ryder, W. D., Zeps, N., Madiredjo, M., Beijersbergen, R., Bernards, R. & Clarke, R. B. 19 Jan

Oncotarget. 2016. 7, 3, p. 2596-2610 14 p.

 

Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44-positive cancer cells.

Aires, A., Ocampo, S. M., Simões, B. M., Josefa Rodríguez, M., Couleaud, P., Spence, K., Latorre, A., Miranda, R., Somoza, Á., Clarke, R., Carrascosa, J. L. & Cortajarena, A. L.

Nanotechnology. 2016. 27, 6, p. 065103

 

Cisplatin selects for stem-like cells in osteosarcoma by activating notch signaling

Yu, L., Fan, Z., Fang, S., Yang, J., Gao, T., Simões, B. M., Eyre, R., Guo, W. & Clarke, R. B

Oncotarget. 2016. 7(22): 33055–33068

 

Intermittent energy restriction induces changes in breast gene expression and systemic metabolism

Harvie, M., Sims, A., Pegington, M., Spence, K., Mitchell, A., Vaughan, A. A., Allwood, W., Xu, Y., Rattray, N., Goodacre, R., Evans, G., Mitchell, E., McMullen, D., Clarke, R. & Howell, A.

Breast Cancer Research. 2016. 18, 1, 57

 

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Koledova, Z., Zhang, X., Streuli, C., Clarke, R. B., Klein, O. D., Werb, Z. & Lu, P.

PNAS. 2016. 113(39)

 

Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis

Eyre, R., Alférez, D. G., Spence, K., Kamal, M., Shaw, F. L., Simões, B. M., Santiago-Gómez, A., Sarmiento-Castro, A., Bramley, M., Absar, M., Saad, Z., Chatterjee, S., Kirwan, C., Gandhi, A., Armstrong, A. C., Wardley, A. M., O'Brien, C. S., Farnie, G., Howell, S. J. & Clarke, R. B.

Journal of Mammary Gland Biology and Neoplasia. 2016. 

 

Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.

Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB.

Cell Rep. 2015 Sep 29;12(12):1968-77. doi: 10.1016/j.celrep.2015.08.050.

 

Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy.

Williams KE, Bundred NJ, Landberg G, Clarke RB, Farnie G.

Stem Cells. 2015 Feb;33(2):327-41. doi: 10.1002/stem.1843.

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, Hedgehog, Wnt, TGFbeta, EGF pathways and other relevant (eg. 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.

Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne A, Caldas C, Clarke RB, De Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A (2014) Patient Derived Xenograft Models: An Emerging Platform For Translational Cancer Research, Cancer Discovery, 4(9):998-1013.

Singh JK, Farnie G, Bundred NJ, Simões BM, Shergill A, Landberg G, Howell SJ and Clarke RB (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, 19 (3); 643-656.

Shaw F, Harrison H, Spence K, Ablett M, Simões BM, Farnie G and Clarke RB (2012) A detailed mammosphere assay protocol for use in the quantification of stem cell activity. Journal of Mammary Gland Biology and Neoplasia, 17(2):111-7.

Harrison H, Farnie G, Howell SJ, Rock R, Stylianou S, Brennan KR, Bundred NJ and Clarke RB (2010) Regulation of breast cancer stem cell activity by signalling through the Notch4 receptor. Cancer Research, 70(2); 709–18.

Sims AH, Smethurst GJ, Hey Y, Okoniewski MJ, Pepper SD, Howell A, Miller CJ and Clarke RB (2008) The removal of multiplicative, systematic bias allows integration of breast cancer gene expression datasets - improving meta-analysis and prediction of prognosis. BMC Medical Genomics, 1:42.

Farnie G, Clarke RB, Spence K, Pinnock N, Brennan K, Anderson NG and Bundred NJ (2007) Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways, JNCI, 99, 616-27.

Stylianou S, Clarke RB and Brennan K (2006) Aberrant activation of Notch signalling in human breast cancer. Cancer Res., 66, 3, 1517-25.

Clarke RB, Spence K, Howell A, Anderson E, Okano H and Potten CS (2005) A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev. Biol., 277, 2, 443-456.

Clarke RB, Howell A, Potten CS and Anderson E (1997) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res., 57, 22, 4987-4991.

Clarke RB, Laidlaw IJ, Jones LJ, Howell A and Anderson E (1993) Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status. Br. J. Cancer, 67, 606-611.