Dr Sandra M Bell

Profile

I obtained my degree in biochemistry from Sussex University and my PhD on colon cancer genetics from Leeds University. Having developed an interest in cancer I then went onto work on positional cloning projects in breast and bladder cancer. I joined the genetics section of the Molecular Medicine Unit in 1996 and worked on a range of projects including the identification of two neurodevelopmental genes MCPH1 and CSMD1. I joined the newly formed section of Ophthalmology and Neuroscience in 2005 establishing my own group investigating the function of the two neurodevelopmental genes MCPH1 and CSMD1 in cancer.

Responsibilities

• Member of School Ethics Committee

Research interests

Our group works on a range of projects including functional studies of two neurodevelopmental genes MCPH1 and CSMD1 in breast and ovarian cancer. We are also investigating drug resistance and cancer stem-like cells in ovarian cancer.

Primary microcephaly (MCPH) (OMIM 251200) is a recessive genetic disorder in which the affected individuals are born with a significantly smaller head size and are mentally retarded. We work on MCPH1 (also called BRIT1), which encodes Microcephalin which contains three BRCA1 carboxyl-terminal (BRCT) motifs. We and co-workers have shown that MCPH1 is involved in DNA repair and regulation of cell cycle checkpoints, particularly the control of entry into mitosis causing premature chromosone condensation.

Figure 1 Mutations in the MCPH1 gene cause microcephaly (A), premature chromosome condensation (B & C) and cancer.

MCPH is thought be a consequence of a mitotic defect during foetal brain development. Abnormalities at mitosis can cause incorrect chromosome organisation and the development of aneuploidy in cancer. Numerous studies have shown that deletions at the MCPH1 (8p22-p23) loci is associated with tumour development and poor prognosis. We therefore propose that, while germ line defects in MCPH1 cause microcephaly, somatic defects may cause cancer (Figure 1).

We have identified reduced Microcephalin expression in both breast and ovarian cancers which is associated with reduced patient survival. We are studying the biological function of Microcephalin to determine how disruption of its activity causes cancer particularly breast and ovarian.

Figure 2 Immunohistochemistry staining of paraffin embedded breast cancer samples. Positive nuclear MCPH1 staining (A), loss of MCPH1 expression (B) and comparison of overall survival based on MCPH1 expression in ductal breast cancer patients (C).

Currently we are utilizing high throughput screening techniques using small molecule and whole human genome siRNA libraries to elucidate the function of MCPH1. I was a founding member of the BioScreening Technology Group (BSTG) established to perform high-throughput, high-content siRNA screens (Reverse Genetics).

CSMD1 (CUB sushi multiple domain protein 1) is a large gene spanning over 2-Mb of chromosome 8p23 (adjacent to MCPH1), which is deleted in many cancer types. A significant amount of evidence points to CSMD1 playing a role in tumour development. We have previously shown that CSMD1 is an independent prognostic factor in breast cancer and we are currently investigating the function of CSMD1 using in vitro and in vivo models.

Ovarian cancer is characterised by late diagnosis, high recurrence of disease and low survival rate. Consequently, women who have undergone surgery for ovarian cancers often have additional chemotherapy to kill residual cancer cells and prevent recurrence. However, relapse often occurs, associated with the development of drug resistance (Figure 3). Ovarian cancer stem like cells (CSCs) are thought to be one mechanism by which tumours become resistant to chemotherapy. Currently we are to trying to identify ovarian CSCs and to investigate how these cells may play a role in drug resistance allowing novel methods to be developed to both identify and kill CSCs, ultimately leading to improved outcome for ovarian cancer patients. My interest in ovarian cancer has led to the establishment in collaboration with clinical colleagues of a tissue bank (now part of the Leeds Multidisciplinary Research Tissue Bank).

Figure 3 (A) Multidrug resistance often develops in cancer cells due to the increased expression of multi drug resistance proteins (MDR) in the cell membrane which export the chemotherapeutic drugs. (B) Immunofluorescence staining of a multidrug resistance protein (green) in an ovarian cancer cell line.

Qualifications

• 1987, BSc (Hons.) Biochemistry, University of Sussex
• 1992, PhD Colon Cancer Genetic, University of Leeds

Professional memberships

• British Association for Cancer Research
• British Society of Cell Biology

Student education

MBChB 1st year - Research Evaluation and Special Studies Project tutor and member of CMT

MBChB 2nd year - Genetics in Medicine

Personal Tutor for 1st & 2nd year MBChB students

Postgraduate Research Tutor for MD/PHD students in Leeds Institute of Medical Research

Lead for International PhD Academy in Medical Research at St James

Research groups and institutes

• Leeds Institute of Medical Research at St James's