A/Prof Colin Clyne
Breast cancer is the most common cause of cancer-related death in women, accounting for 25% of new cancers in Australian women. Most (75%) patients have oestrogen-dependent (ER+) disease that responds to anti-oestrogen hormone therapy and has a better prognosis than oestrogen-independent (ER-) cancer. However, the greater incidence of ER+ tumours means that more women die from ER+ breast cancer than from any other subtype.
The predominant strategies to block oestrogen signalling in ER+ tumours are to selective estrogen receptor modulators (SERMs, that block oestrogen action) and/or aromatase inhibitors (that block oestrogen production). However, not all ER+ tumours respond to endocrine therapy, and most that do eventually become resistant – after which few treatment options remain. The lack of reliable markers to predict which patients will respond to tamoxifen – and which will exhibit resistance – represents a major unmet need.
This work centres on a novel protein known as timeless that has been reported by others to differentiate between tamoxifen responders and non-responders. The underlying mechanisms or relevance of this association are unknown.
In this paper we showed that timeless binds to the oestrogen receptor and stimulates its activity. This provides the first direct link between timeless and oestrogen / tamoxifen, and may explain the clinical associations outlined above.
Centre for Endocrinology and Metabolism
Cancer Drug Discovery
Journal and article title
Timeless has been reported to differentiate between tamoxifen responders and non-responders. We have uncovered new molecular mechanisms underlying this association, thereby providing a rational basis for development of this protein as a marker of response to SERMs. This work has the potential to validate Timeless as a clinical marker to identify those patients at risk of developing resistance to SERMs, who may be better served by other approaches, e.g. aromatase inhibitors.