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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

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

Member of the British Association for Cancer Research (BACR) Executive Committee, 2012-2015.


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. [Epub ahead of print]


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.


The role of steroid hormones in breast cancer stem cells.

Simoes BM, Alferez D, Howell S, Clarke RB.

Endocr Relat Cancer. 2015 Sep 17. pii: ERC-15-0350.


The seventh ENBDC workshop on methods in mammary gland development and cancer.

Glukhova MA, Hynes N, Vivanco Md, van Amerongen R, Clarke RB, Bentires-Alj M.

Breast Cancer Res. 2015 Sep 2;17(1):119. doi: 10.1186/s13058-015-0629-5.


Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells.

Lamb R, Ozsvari B, Bonuccelli G, Smith DL, Pestell RG, Martinez-Outschoorn UE, Clarke RB, Sotgia F, Lisanti MP.

Oncotarget. 2015 Sep 8;6(26):21892-905.


Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy.

Lamb R, Fiorillo M, Chadwick A, Ozsvari B, Reeves KJ, Smith DL, Clarke RB, Howell SJ, Cappello AR, Martinez-Outschoorn UE, Peiris-Pagès M, Sotgia F, Lisanti MP.

Oncotarget. 2015 Jun 10;6(16):14005-25.


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.


Biological interpretation of genome-wide association studies using predicted gene functions.

Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK; Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Boehnke M, Raychaudhuri S, Fehrmann RS, Hirschhorn JN, Franke L.

Nat Commun. 2015 Jan 19;6:5890. doi: 10.1038/ncomms6890.


Co-ordination of cell cycle, migration and stem cell-like activity in breast cancer.

Lamb R, Lisanti MP, Clarke RB, Landberg G.

Oncotarget. 2014 Sep 15;5(17):7833-42.


Patient-derived xenograft models: an emerging platform for translational cancer research.

Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A.

Cancer Discov. 2014 Sep;4(9):998-1013. doi: 10.1158/2159-8290.CD-14-0001.


17ß-estradiol regulates giant vesicle formation via estrogen receptor-alpha in human breast cancer cells.

Wright PK, Jones SB, Ardern N, Ward R, Clarke RB, Sotgia F, Lisanti MP, Landberg G, Lamb R.

Oncotarget. 2014 May 30;5(10):3055-65.


A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity.

Ablett MP, O'Brien CS, Sims AH, Farnie G, Clarke RB.

Oncotarget. 2014 Feb 15;5(3):599-612.

Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS).

Farnie G, Johnson RL, Williams KE, Clarke RB, Bundred NJ.

Cell Cycle. 2014;13(3):418-25. doi: 10.4161/cc.27201.


Targeting IL-8 signalling to inhibit breast cancer stem cell activity.

Singh JK, Simões BM, Clarke RB, Bundred NJ.

Expert Opin Ther Targets. 2013 Nov;17(11):1235-41. doi: 10.1517/14728222.2013.835398.


Wnt pathway activity in breast cancer sub-types and stem-like cells.

Lamb R, Ablett MP, Spence K, Landberg G, Sims AH, Clarke RB.

PLoS One. 2013 Jul 4;8(7):e67811. doi: 10.1371/journal.pone.0067811.


Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity.

Lamb R, Lehn S, Rogerson L, Clarke RB, Landberg G.

Cell Cycle. 2013 Aug 1;12(15):2384-94. doi: 10.4161/cc.25403.


Combined inhibition of ErbB1/2 and Notch receptors effectively targets breast ductal carcinoma in situ (DCIS) stem/progenitor cell activity regardless of ErbB2 status.

Farnie G, Willan PM, Clarke RB, Bundred NJ.

PLoS One. 2013;8(2):e56840. doi: 10.1371/journal.pone.0056840.


Combining Notch inhibition with current therapies for breast cancer treatment.

Brennan K, Clarke RB.

Ther Adv Med Oncol. 2013 Jan;5(1):17-24. doi: 10.1177/1758834012457437.


Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ER-a status.

Harrison H, Rogerson L, Gregson HJ, Brennan KR, Clarke RB, Landberg G.

Cancer Res. 2013 Feb 15;73(4):1420-33. doi: 10.1158/0008-5472.CAN-12-2505.


Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms.

Singh JK, Farnie G, Bundred NJ, Simões BM, Shergill A, Landberg G, Howell SJ, Clarke RB.

Clin Cancer Res. 2013 Feb 1;19(3):643-56. doi: 10.1158/1078-0432.CCR-12-1063.


"The charmingest place": Non-coding RNA, lineage tracing, tumour heterogeneity, metastasis and metabolism - new methods in mammary gland development and cancer: the fifth ENBDC Workshop.

Clarke RB, Stingl J, Vivanco M and Bentires-Alj M (2013)

Breast Cancer Research, 15(5), 330.


A detailed mammosphere assay protocol for the quantification of breast stem cell activity.

Shaw FL, Harrison H, Spence K, Ablett MP, Simões BM, Farnie G, Clarke RB.

J Mammary Gland Biol Neoplasia. 2012 Jun;17(2):111-7. doi: 10.1007/s10911-012-9255-3.


Stem cells in breast tumours: are they ready for the clinic?

Ablett MP, Singh JK, Clarke RB.

Eur J Cancer. 2012 Sep;48(14):2104-16. doi: 10.1016/j.ejca.2012.03.019.


Breast cancer stem cells and their role in resistance to endocrine therapy.

O'Brien CS, Farnie G, Howell SJ, Clarke RB.

Horm Cancer. 2011 Apr;2(2):91-103. doi: 10.1007/s12672-011-0066-6.


Breast cancer stem cells: something out of notching?

Harrison H, Farnie G, Brennan KR, Clarke RB.

Cancer Res. 2010 Nov 15;70(22):8973-6. doi: 10.1158/0008-5472.CAN-10-1559.


Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy.

Thompson AM, Johnson A, Quinlan P, Hillman G, Fontecha M, Bray SE, Purdie CA, Jordan LB, Ferraldeschi R, Latif A, Hadfield KD, Clarke RB, Ashcroft L, Evans DG, Howell A, Nikoloff M, Lawrence J, Newman WG.

Breast Cancer Res Treat. 2011 Jan;125(1):279-87. doi: 10.1007/s10549-010-1139-x.

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.

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.

Blance RN, Sims AH, Anderson E, Howell A and Clarke RB (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):257-64.

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.

Howell SJ, Anderson E, Hunter T, Farnie G and Clarke RB (2008) Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity. Breast Cancer Res, 10(4):R68.

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, Anderson E, Howell A and Potten CS (2003) Regulation of human breast epithelial stem cells. Cell Proliferation, 36, supp. 1, 45-58.

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.

Laidlaw IJ, Clarke RB, Howell A, Owen AWMC, Potten CS and Anderson E (1995) The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology, 136, 164-171.

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.