(MCRC Clinical) Finding the Achilles' Heel of Drug-Resistant Breast Cancer: Exploiting Synthetic Lethal Vulnerabilities in Transcription Factor Signalling

About the project

About the Project Breast cancer is the most common cancer in women. Every year in the UK, around 55,000 patients are diagnosed with breast cancer, and only 23% of them have preventable disease. Around 70% of breast cancers are driven by the estrogen receptor (ER). Drugs which block the effects of the estrogen receptor reduce the risk of recurrence. Although they are initially effective, the risk of recurrence persists for at least 20 years after diagnosis, leading to incurable disease and death. Hence, understanding how a drug fails is vital to increase patient survival. Gene expression plays an essential role during cancer progression. This process is regulated by various means, importantly by proteins that can open/close chromatin, called chromatin remodeller complexes (CRC). CRC proteins are inactivated by mutations in treatment-resistant breast cancers, leading to a poorer outcome. We found in our previous study that cells stop responding to these treatments when they lose CRC. We also identified a specific class of transcription factors that are hyperactivated in patients with ER and CRC loss. We believe that their hyperactivity causes these patients to stop responding to drugs. Hence, targeting these transcription factors may affect cells with deregulated signalling due to CRC or ER loss; therefore, the strategy can be used to sensitise drug-resistant cancers without affecting normal cells. In this study, the student will test this idea by modifying cancer and normal cells to reduce transcription factor protein levels during existing therapies, and will identify the important proteins activated by these transcription factors and drugs that block them. These drugs might stop cancer growth in patients with reduced CRC and ER levels, revealing opportunities for personalised medicine and targeted therapeutics that could improve patient survival. The research will provide opportunities to advance drug discovery/development, thereby potentially positioning the clinical student’s development towards clinical trials. Eligibility You must be a post-registration clinician and therefore must hold an MBChB degree or equivalent medical degree and ideally have a specialist post in a related subject, to apply for our Clinical Research Training Fellowships. It is generally expected that CRTFs will return to a training programme in the UK upon completion of their research degree. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University's Country Specific information page. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply Apply directly via this link: https://tinyurl.com/577zjazd or on the online application portal, select MCRC PhD Programme as the programme of study. You may only apply for one project within this scheme. Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV) Supporting Statement Academic Certificates and Transcripts Incomplete or late applications will not be considered. Further details are available on our website: CRUK Manchester Centre PhD Training Scheme | Biology, Medicine and Health | University of Manchester Application Timeline Applications open: Monday, 5 October 2026 Application deadline: Monday, 23 November 2026 Interview date: Week commencing 11 January 2027 Start date: September 2027 Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/”

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