(MCRC Non-Clinical) Elucidating progesterone-driven Wnt signalling for breast cancer prevention

About the project

About the Project Progesterone signalling is essential for normal breast development, but repeated hormone-driven expansion of progenitor cells may also create cellular states that initiate breast tumours. Our recent work (Simões et al, Nature, 2025)shows that blocking progesterone activity in normal human breast tissue reduces Wnt ligand secretion, progenitor activity and collagen-rich extracellular matrix, shifting the tissue away from a cancer-risk-associated state and towards changes that are favourable for breast cancer prevention. This PhD will investigate how progesterone-driven signalling between Wnt5A and its receptor ROR2 regulates epithelial progenitor behaviour, stromal crosstalk and tissue architecture in the human breast, with the long-term goal of identifying pathways that could be targeted for breast cancer prevention. Across three integrated aims, the student will use complementary human breast models and analytical approaches, including immortalised epithelial and fibroblast models, ex vivo organoid and explant systems, functional perturbation of Wnt signalling, epigenomic profiling and spatial singlecell analysis. First, the student will define how Wnt5A-ROR2 signalling affects epithelial plasticity, luminal progenitor-like activity, fibroblast responses and collagen expression (Aim 1). They will then map progesterone-driven epigenetic changes that regulate Wnt ligands across key epithelial populations (Aim 2). Finally, they will test whether blocking ROR2 signalling or progesteroneinduced epigenetic regulators can reverse progenitor expansion and matrix remodelling in intact human breast tissue models (Aim 3). The project is directly aligned with the MCRC-CRUK Manchester Centre strategy by addressing early biological events that may precede tumour formation. It will provide outstanding training in cancer prevention biology, hormone signalling, breast tissue models, functional genomics and spatial technologies, while generating mechanistic insight into pathways that could help prevent breast cancer initiation. Eligibility You must hold, or about to obtain, a minimum Upper Second Class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. A related master’s degree would be an advantage 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/

Research areas