Breast cancer growth is estrogen- regulated in many cases. Estrogen actions
are mediated by estrogen receptors ERα and ERβ. Whilst the involvement of ERβ in
breast cancer is unresolved at present, up to 80% of breast tumours are ERα-
positive and likely to respond to endocrine therapies, such as anti-estrogens.
However, a substantial proportion of patients develop a resistance to such
treatments. Most resistant tumours continue to express ERα and many will respond
to an alternative hormonal therapy, indicating that ERα continues to be important
following the emergence of resistance. One proposed mechanism for endocrine
resistance is post-translational modification of the ERα, particularly phosphorylation
of ERα within the transcription activation domain AF1.
This project investigates how the phosphorylation at residues within the AF1
domain is linked to ERα activation and tumour cell growth in the presence of
tamoxifen and in the absence of ligand, by stable introduction of ERα
phosphorylation site mutants in the MCF7 human breast cancer cell line, commonly
used as a model for ERα-positive breast cancer. Characterisation of these lines
suggests that phosphorylation at the sites within the AF1 domain of the ER increases
the agonist activity of tamoxifen. Further studies to determine the mechanisms by
which ERα activity is regulated by phosphorylation within AF1 are discussed.