Supervisor: Dr Graham Neill
Hedgehog (HH) signalling represents a major developmental pathway that is implicated in the biology of an increasing number of tumour types (e.g. skin, brain, pancreas, breast and prostate) and this is linked to its role in regulating stem cell populations and other cellular mechanisms. Aberrant activation of HH signalling results in increased expression of the downstream proto-oncogenic GLI (GLI1 and GLI2) transcription factors which are the principal effectors of HH signalling (1). In prostate cancer, the level of GLI1 expression correlates positively with tumour progression but how its oncogenicity is manifest remains largely unknown (2). The main issues associated with prostate cancer are identifying the cells that drive tumour formation/progression (i.e. cancer stem cells) as well as understanding how tumours acquire resistance to anti-androgen therapy.
We have recently determined that ectopic GLI1 expression confers androgen-independence and a more aggressive phenotype to the androgen-dependent LNCaP prostate cancer cell line (unpublished data). Interestingly, a separate study has recently shown that ectopic GLI1 confers oestrogen-independence to the oestrogen-dependent MCF-7 breast cancer cell line (3). As such, tumours that are initially hormone-dependent and that respond to anti-hormonal treatments (e.g. Casodex or Tamoxifen) may become resistant to these therapies if the tumours subsequently express high GLI1 levels.
The aim of this project is to help determine the precise cellular mechanism(s) by which GLI1 promotes hormone-independence in LNCaP and/or MCF-7 cancer cell lines with the prolonged goal of identifying new targets that will increase the efficacy of anti-hormonal treatment. The student will learn various techniques including cell culture, Western blotting, (q)PCR, RNA interference and immunological staining of cultured cells and tumour samples.
1. Kasper, M., et al., GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer, 2006. 42(4): p. 437-45.
2. Karhadkar, S.S., et al., Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 2004. 431(7009): p. 707-12.3. Zhao, J., et al., Expression of Gli1 correlates with the transition of breast cancer cells to estrogen-independent growth. Breast Cancer Res Treat, 2009. (Epub ahead of print)