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(MCRC Non-Clinical) Using ex vivo models to determine early transcriptome changes in breast cancer


Faculty of Biology, Medicine and Health

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Prof K R Brennan , Dr A Gilmore , Dr A Ucar , Dr S Howell No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Breast cancer remains the most common female cancer worldwide and the second leading cause of death due to cancer in women within the UK. However, we still know very little about the initiation of breast cancer, which is limiting the development of novel preventative treatments. Around 90% of breast cancer cases are sporadic. However, there is no obvious carcinogen or driver mutation, unlike other cancers. This raises questions about how the mutations required to initiate breast cancer arise and what are the transcriptional changes associated with initiation.

Our recent work seeking to understand how high mammographic density increases breast cancer risk has shown that the increased tissue stiffness associated with high mammographic density alters cellular metabolism resulting in an accumulation of reactive aldehydes. These reactive aldehydes lead to DNA damage and cellular transformation. Our preliminary work looking at proteomic differences between normal and Her2-overexpressing murine mammary ducts has also highlighted an increase in fatty acid metabolism within Her2-overexpressing ducts. These results lead us to hypothesise that a consistent change in early breast cancer is metabolism, leading to the generation of reactive species that drive mutation.

We will use 3D ex vivo models to culture intact murine mammary ducts and expose them to different oncogenic insults, a stiffened extracellular matrix to mimic high mammographic density, the over expression of ER or Her2, and the loss of BRCA1. We will then complete a transcriptomic analysis to determine the transcriptional and pathway changes that occur early after an oncogenic insult. We will also establish which of these changes are essential for breast cancer initiation.

Entry Requirements:
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the CRUK Manchester Centre PhD Training Scheme (MCRC) website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mcrc-training-scheme/

General enquiries can be directed to [Email Address Removed].

Equality, diversity and inclusion is fundamental to the success of The University of Manchester and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Interview date – 8 January 2021

Funding Notes

Funding will cover UK tuition fees/stipend only (currently at £19,000 per annum) and running expenses. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable a limited number of full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

The duration of this project is four years to commence in October 2021.
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