Investigating extracellular matrix stiffness as a risk factor for breast cancer

Closing date: 15/03/2027

MB-PhD Studentship: Investigating extracellular matrix stiffness as a risk factor for breast cancer

Lead Supervisors: Professor Sacha Howell
Lead Supervisors: Dr Andrew Gilmore, Dr Hannah Harrison, Dr Hongpeng Zhou

Applications Deadline: Monday 15th March 2027
Interviews: Week commencing 3rd May 2027
Start date: September 2027

Project Keywords: Breast cancer prevention, tamoxifen, extracellular matrix
Research Opportunity: MB-PhD Studentship

Project Outline

Breast cancer (BC) is the leading cause of death for UK women under 50. Around 90% of cases are sporadic, raising questions about the aetiology of genomic damage required to initiate BC. One of the largest risk factors for BC is high mammographic density (MD), determined by the amount of radiopaque tissue seen on a mammogram. regions of high MD are where the collagenous extracellular matrix (ECM) that supports the epithelial ducts is mechanically stiffer.

This elevated ECM stiffness in is directly linked to increased breast cancer risk. Furthermore, recent work from our groups has shown that targeting hormone signalling in high-risk women results in significant remodelling of the periductal and perilobular ECM, in particular collagen isoforms that are associated with MD density and stiffness. Thus, BC risk prevention strategies result in changes in breast ECM composition. However, our mechanistic understanding of how ECM mechanics result in elevated risk is incomplete. 

One significant issue around studying ECM and BC risk is the lack of experimental models. Cell culture models allow for modification of ECM mechanics but are simplistic compared to native tissue composition. Mouse models do not recapitulate the collagen rich stromal ECM of human breast, and human tissue biopsies cannot be experimentally manipulated. To overcome these limitations the supervisory team has developed a human breast explant model which can be maintained for up to 14 days in culture, and which retains ECM and tissue organisation.

We will use this model to interrogate how localised changes in ECM composition and mechanics affect cell function and markers of cancer risk. The student will develop approaches for modifying and measuring ECM mechanics within the explant model, and use this to identify target pathways for linking ECM mechanics and cancer risk from our existing spatial transcriptomic data.

Applications for this project are now open. Please complete your application on The University of Manchester Postgraduate Application Portal.

About Prof. Sacha Howell (project Lead Supervisor)

Professor Howell is a Consultant Medical Oncologist specialising in the treatment and prevention of breast cancer. He is director of the Manchester Breast Centre and the Prevent Breast Cancer Research nuit. He trained as a medical oncologist at The Christie, Manchester and gained his PhD studying the role of prolactin in breast cancer stem cell regulation, at the University of Manchester. He has extensive experience in the design and implementation of both cancer treatment and prevention clinical trials.

Professor Howell has developed a platform for the study of preventive approaches through serial breast biopsies and imaging in women at increased risk. Through this approach his team are making significant progress in understanding the mechanisms of action and resistance to existing and novel breast cancer preventive approaches. Through close collaboration with basic scientists in The Manchester Breast Centre, and international collaborators, significant progress is being made in understanding these mechanisms and how mammographic density relates to tissue features, leading to cellular transformation.

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Sacha Howell headshot

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