Breast Cancer
(Molecular Pharmacology) Group
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Director of research: Professor R.I. Nicholson

Our research is generously funded by:-

Welcome to the Breast Cancer Group at the Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University.

In the treatment of breast cancer, anti-cancer agents are increasingly being targeted to molecular pathways which govern the aberrant behaviour of the cancer cells. This is best exemplified by oestrogen receptor (ER) targetting with anti hormones, and HER2 amplification which is targeted by herceptin. However, a continuing clinical problem with all targeted treatments is intrinsic and acquired drug resistance which can result in poorer patient outlook.

Building on our group's international track record in anti-hormone resistance, we have recently focused our studies around deciphering drug-induced signalling. Such events are able to limit the anti-tumour action of currently-used cancer drugs and drive resistance. Studies in this novel research area have considerable potential to reveal molecular profiles enabling modern anti-cancer agents to be more accurately targeted to the responsive or resistant patient cohort. Critically, they can also identify signalling targets for innovative therapeutic strategies to control breast cancer growth and progression. Our research utilises unique resistant cell models developed in house and clinical breast cancer samples from antihormone responsive and resistant patients.

  Mitotic activity in a drug resistant breast cancer cell model.Mitotic spindles imaged by red staining of beta tubulin with chromosome rearrangement stained blue.

Main Areas of Research  

Deciphering growth signalling in antihormone resistant cells to find novel drug targets and biomarkers
(
Dr. J.M.W. Gee, Prof. R.I. Nicholson )

Prof. Rob Nicholson and Dr. Julia Gee lead experimental and translational breast cancer research centred on defining key molecular mechanisms that limit maximal initial response to anti hormone agents and that drive therapeutic resistant growth. Further specific interests lie in the area of "drug-induced" signalling pathways and Triple Negative breast cancer.
Dr. Gee's specific focus, funded through a Breast Cancer Campaign research fellowship award, is to explore the impact of prolonged anti hormone treatment (as would be experienced in the adjuvant disease setting) on the resultant anti hormone resistant growth signalling mechanisms. This is being achieved by (i) developing a novel panel of in vitro breast cancer cell lines to model treatment of multiple ER+ breast cancer phenotypes for at least 3 years with major classes of anti hormone agent and (ii) direct profiling of gene expression in clinical breast cancer relapse material.
In defining key signalling pathways, the ultimate goals of studies in this research area are to define novel therapeutic targets and clinical biomarkers relevant to improved selection and pharmacological treatment of anti hormone resistant patients.

Tyrosine kinase genes altered in 3 anti hormone resistant cell models versus responsive MCF7 cells.
(red=increased, green=decreased)

The following translational projects are also carried out in our laboratories in collaboration with scientists, clinicians and industry :
• Profiling GFRalpha/RET signalling in breast cancer in the clinic and in vitro.
• Targeting erbB, mTOR and RET signalling pathways in anti hormone resistant breast cancer cell models
• Profiling CD44 and its variants within clinical breast cancer sample series 


HER2 signalling (brown) in breast cancer from an anti hormone resistant patient






















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Invasive signalling in anti hormone resistant breast cancer  ( Dr. S. Hiscox )

Dr. Steve Hiscox (an RCUK Academic Fellow) oversees experimental and translational research centred on understanding the association between anti hormone resistance and the development of an aggressive cell phenotype in breast cancer which clinically can result in poorer patient outlook. Specifically, his research goals are to determine how anti hormone resistance influences the invasive, migratory and angiogenic nature of breast cancer cells, and to investigate the interactions between tumour cells and stromal components in order to identify the potential of key elements within these pathways as prognostic indicators and therapeutic targets to control progression.

Current research projects include:
• Elucidating the role of CD44 in anti hormone response and resistance in vitro
• The prognostic and predictive value of cell adhesion molecules in clinical breast cancer
• Investigating the targeting potential of focal adhesion kinase (FAK) in HER2+ and HER2- breast cancer
• Angiogenic responses of acquired anti hormone-resistant breast cancer cells
• Wnt signalling and anti hormone resistance
• Influence of stromal environment on drug response




Compared with anti hormone responsive cells (above), resistant models (below) grow in loose colonies of angular cells and are highly invasive
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Zinc signalling and its potential as a novel therapeutic target in anti hormone resistance 
 ( Dr. K.M. Taylor )

    
                                    

                               
Dr. Kathryn Taylor
is currently involved in 2 main research areas:-

  • The mechanism of zinc transporter function and its effect on zinc signalling
    The primary focus of Dr. Taylor's research program, funded through a Wellcome Trust University Research award, is investigating the mechanism of zinc transporter function in cells, and specifically how zinc and zinc transporters can control biological processes within cells. With particular emphasis placed on the zinc transporters from the ZIP family, also known as SLC39A , these studies include identification, function, and signaling mechanisms of transporters primarily at the protein level. Genetic manipulation techniques, cell biological methods and fluorescent microscopy form the basis of the technologies used to investigate these molecules as well as more recently emerging techniques to investigate protein associations within cells.
  • The role of intracellular zinc in driving aggressive anti hormone resistant breast cancer
    Dr. Taylor's other major research interest lies in the investigation of the exact role of the ZIP family of zinc transporters in breast cancers with acquired tamoxifen resistance, a disease state which can result in women suffering a recurrence of breast cancer in a more aggressive form. In particular, research is concentrated on the differential expression and activation of such ZIP family zinc transporters and how they are affected by a variety of clinically relevant treatments.
    More recent research has discovered a role for phosphorylation of these zinc transporters as their mechanism of activation which opens the door for clinical blockade using small molecule inhibitors. An alternative approach is the generation of unique ZIP transporter antibodies which may provide a means of predicting patients at risk of developing anti-hormone resistance.

 

 

 

 

 

 


Differential location of two zinc transporters
(stained red or green)
in breast cancer cells


 

 

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