Print this page 
Nuclear receptor pharmacology
Summary
Oestrogen receptor blockers are very successful breast cancer treatments; however, not all patients respond to these drugs and many that do eventually become resistant to their effects. We are identifying alternative molecules related to the oestrogen receptor that could be exploited as novel breast cancer therapeutics.
Description
The 48 human nuclear receptors transduce cellular signals into changes in gene expression, and influence virtually all aspects of cell biology. Typified by the steroid hormone and vitamin D receptors, nuclear receptors are ideal targets for drug discovery. Half of all nuclear receptors, however, are "orphans" that have no endogenous ligand to target in a conventional pharmacological sense.
LRH-1 is one such orphan receptor that is an attractive new target for breast cancer therapy by virtue of its ability to induce cell proliferation, invasion and cancer stem cell-like phenotypes.
We have shown that LRH-1 activity can be inhibited by peptides that block its interactions with other co-regulator proteins, and are currently using in silico and structural approaches to design small drug-like molecules that act in the same manner. These are the first LRH-1 antagonists to be described.
Funding
National Health and Medical Research Council
National Breast Cancer Foundation
Cancer Council Victoria
Victorian Breast Cancer Research Consortium
Selected Publications
Miki Y, Clyne CD, Suzuki T, Moriya T, Nakamura Y, Ishida T, Yabuki N, Kitada K, Hayashi S-i, Sasano H (2006) Immunolocalization of liver receptor homologue-1 (LRH-1) in human breast carcinoma: possible regulator of in situ steroidogenesis. Cancer Lett 244: 24-33
Safi R, Kovacic A, Gaillard S, Murata Y, Simpson ER, McDonnell DP, Clyne CD. (2005). Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res 65:11762-70
Zhou J, Suzuki T, Kovacic A, Saito R, Miki Y, Ishida T, Moriya T, Simpson ER, Sasano H, Clyne CD (2005) Interactions between Prostaglandin E2, Liver Receptor Homologue-1 (LRH-1) and aromatase in breast cancer. Cancer Res 65:657-63
Kovacic A, Speed CJ, Simpson ER, Clyne CD (2004) Inhibition of aromatase transcription via promoter II by Short Heterodimer Partner (SHP) in human preadipocytes. Mol Endocrinol 18:252-259
Clyne CD, Speed CJ, Zhou J, Simpson ER (2002) Liver Receptor Homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem 277: 20591-20597