Professor Simak Ali
Hormone resistance in breast cancer
Estrogens regulate breast cancer growth, with 70-80% of breast tumours expressing estrogen receptor-a (ER) and ER-positive breast cancers respond to endocrine therapies. However, resistance (de novo or acquired) is responsible for the deaths of a high proportion of patients with ER-positive breast cancer. Importantly, following emergence of resistance in patients treated with the anti-estrogen tamoxifen, many patients will respond to other endocrine treatments, for example the anti-estrogen Faslodex, or to aromatase inhibitors, implying a continued role for ER in endocrine resistant breast cancer. ER is a transcription factor that acts by regulating the expression of estrogen-regulated genes upon binding estrogen. Anti-estrogens compete with estrogen for binding to ER, to inhibit its activity. We are investigating the molecular mechanisms by which altered regulation of ER is important in mediating endocrine response and resistance, through investigation of (a) post-translational modification in stimulating ER activity, (b) the role of transcriptional co-regulator proteins, in particular the Amplified in Breast Cancer 1 (AIB1) gene in crosstalk with ER and EGFR/HER2, and (c) identification of estrogen-regulated genes as potential important new therapeutic targets for the treatment of endocrine resistant breast cancer. Recent highlights from our work include (i) the identification of an ER co-regulator that represses ER activity, and which appears to act as a tumour suppressor gene in ER-positive breast cancer (Lopez-Garcia et al 2006 NAR; also see Wortham et al 2009 Oncogene), (ii) the demonstration that phosphorylation of ER at specific sites is associated with response and resistance to tamoxifen (Sarwar et al. Endocrine Rel Cancer 2006; Jiang et al Clin Cancer Res 2007), (iii) the identification of CDK7 as a key protein kinase regulating ER activity and the generation of the first CDK inhibitor, which selectively inhibits CDK7 (Ali et al 2009 Cancer Research), (iv) the development of endocrine resistant breast cancer cell lines (Tolhurst et al 2010 Breast Cancer Research & Treatment) and (v) the identification of a new mediator of breast cancer cell growth known as LRH-1, which acts by regulating ER expression in breast cancer cells. LRH-1 is also known to regulate aromatase expression; therefore our findings make LRH-1 a key regulator of estrogen responses in breast cancer cells (Thiruchelvam et al Breast Cancer Research & Treatment 2010). On the basis of our findings, we are developing assays for the identification of LRH-1 inhibitors as a new therapeutic approach in breast cancer, through a drug discovery program with the Dept of Chemistry at Imperial College.
The clinical specialty relevant to: Oncology
http://www1.imperial.ac.uk/medicine/people/simak.ali/
http://www1.imperial.ac.uk/medicine/research/institutes/drugdiscoverycentre/cd3/
Contact Details
simak.ali@imperial.ac.uk
Tel: +44 (0)20 8383 3789
