GW4 BioMed MRC DTP PhD Studentship: Fetal-maternal genetic interactions and the effects of maternal age at first pregnancy on breast cancer susceptibility

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 19 studentships for entry in September/October 2018.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. The training programme has three strands: research skills; professional and career development skills; and opportunities to broaden horizons, which might include placements, research visits, public engagement internships and a mini-MD programme of bespoke clinical exposure.

Supervisory team for this project:
Dr Adele Murrell (Bath), Prof Rosalind John (Cardiff), Dr Matt Smalley (Cardiff) and Dr Gemma Sharp (Bristol)

Project description:

Several studies have shown that the age of a woman at her first full-term pregnancy impacts on her life-long breast cancer risk. Below the age of 20, there is a protective effect. By 25, there is a very slight increase in risk around childbirth before the protective effect starts. After 25 the protective effect is reduced. Women who give birth for the first time at 35 do not benefit from this protection and actually have a higher breast cancer risk than women who have never given birth. Indeed early pregnancy has been shown to induce a genomic expression profile that is still identifiable in post-menopausal breast tissue. Genes within this signature include transcription factors and genes encoding proteins with functions in apoptosis and DNA repair. However we still know very little about the genetic interactions regulating the balance of fetus-driven placental growth factors and their impact on maternal mammary gland differentiation during pregnancy. There is also no information about whether placental growth factor levels differ according to maternal age. About 95 placental and fetal growth regulating factors are encoded by imprinted genes (i.e. they have an epigenetic dosage-compensation mechanism that results in transcription of only one parental allele). This PhD project will examine expression levels of imprinted genes in placental tissue relative to endocrine growth hormone levels and insulin signalling markers in maternal serum during different stages of pregnancy, in women of different age groups who are pregnant for the first time (n=1085 women).

Ethical permission has been approved for the use of placental tissue and matched maternal serum from 1085 suitable donors to the BabyBioBank. The placenta samples will be assayed for imprinted DNA methylation and expression using pyrosequencing assays and targeted RNA sequencing. The matched maternal serum samples will be analysed by mass spectrometry to correlate imprinted gene expression levels in placenta with growth factors and hormone levels in maternal serum. These data will be compared to gene expression profiles in normal and tumour tissues of breast cancer patients. Publically available breast cancer data sets such as the METABRIC project will be used for this analysis. Samples from the breast cancer clinic at RUH will be used to validate the expression of selected genes identified in the above analysis. Mouse models with placental insufficiency due to engineered disruption of imprinted genes are available. These mice will be profiled as above to examine concurrent expression of the developing mammary gland and placentae during gestation and after birth in order to functionally address placental-mammary co-development.

The results of this project will provide valuable information of the fetal-maternal gene circuits and their role in influencing mammary gland differentiation. Future studies will examine whether these gene circuits confer protection against breast cancer.


IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bath.