Fetal-maternal genetic interactions and the effects of maternal age at first pregnancy on breast cancer susceptibility

A woman's age at 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 an increase in risk around childbirth before the protective effect starts; after 25 the
protective effect is reduced. Women who give birth at 35 have a higher breast cancer risk than nulliparous women.
Early pregnancy induces a genomic expression profile that is still identifiable in post-menopausal breast tissue, and
includes transcription factors and genes encoding apoptosis- and DNA repair-related proteins. However, little is
known about the impact of fetus-driven placental growth factors on maternal mammary gland differentiation during
pregnancy, or the genetic interactions that regulate them. It is not known whether placental growth factor levels differ
with maternal age.
About 95 placental and fetal growth regulating factors are encoded by imprinted genes. This 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
experiencing a first pregnancy.
Placental tissue and matched maternal serum samples are available from BabyBioBank. Placenta samples will be
assayed for imprinted DNA methylation and expression using pyrosequencing assays and targeted RNA sequencing.
Matched maternal serum samples will be analysed by mass spectrometry to correlate placental imprinted gene
expression with serum growth factors and hormone levels. These data will be compared to gene expression profiles
in normal and tumour tissues of breast cancer patients using publicly available data sets such as the METABRIC
project. Samples from the breast cancer clinic at RUH will be used to validate expression of selected genes identified
in the analysis.
The results will provide valuable information on fetal-maternal gene circuits and their influence on m ammary gland
differentiation. Future studies will examine whether these gene circuits confer protection against breast cancer. This
is a particularly pertinent project when women are tending to delay childbearing: in 1970, the average age of first
pregnancy was 21.4 years; in 2013 it was 30.3 years. Between 2002-2004 and 2011-2013, female breast cancer
incidence rates (age standardised) have increased by 6%. As women delay having children the risk for breast cancer
will increase, therefore this approach to understanding whether placental development influences risk by altering
mammary gene expression profiles would lead to improved maternal health outcome and lifelong health.
The project falls within the MRC strategic research priorities of "improved health outcome" and "genetics approach to
understand lifelong health". Pregnant women are a priority in public health screening programs to ensure improved
health outcome for the next generation.
The project provides cross-disciplinary research training, including in experimental design and statistics to carry out a
population study using the available placenta and maternal serum samples. It aligns with MRC DTP goals prioritising
cross-cutting skills areas such as quantitative skills and in vivo science. The supervising team matches the aim to
support collaboration across the GW4 the partner institutions, and includes early career researchers