Endocrinology

Our aim

Our overall aim is to understand the molecular mechanisms that underpin the response and resistance of oestrogen receptor positive (ER+) breast cancer to oestrogen deprivation.

Overview

Over 70% of breast cancer patients at primary diagnosis have breast tumours that express the ER and proliferate in response to oestrogen (E). E-bound ER associates classically with oestrogen response elements (ERE) on target genes controlling proliferation and cell survival. This has been exploited clinically by the development of endocrine therapies. These seek to deprive the hormone dependent tumour cells of E using aromatase inhibitors, which block the conversion of androgens into Es (reviewed by Dowsett & Howell, 2002) or the use of antioestrogens such as the selective oestrogen receptor modulator (SERM) tamoxifen or ICI182780 (fulvestrant) both of which compete with E for the ER. Endocrine therapy is the mainstay of treatment for patients with ER+ disease: 5-years’ tamoxifen treatment leads to absolute reductions in recurrence and mortality after 10 years of 14% and 7%, respectively.

It seems certain that endocrine therapy will remain an obligate component of treatment for ER+ breast cancer for the foreseeable future. We have helped demonstrate that oestrogen deprivation with third-generation aromatase inhibitors (AIs) is the most effective means of endocrine treatment of ER+ breast cancer in postmenopausal women. Unfortunately, the beneficial actions of AIs, like those of other endocrine treatments, are often attenuated either de novo or by acquisition of mechanisms that circumvent the need for oestrogen but in most cases, retain ER.

While many putative pathways of resistance have been uncovered in in vitro studies, particularly for tamoxifen, few have been confirmed clinically and there is a paucity of studies of resistance to E-deprivation with AIs. Multiple new agents affecting cell signalling pathways are in clinical use or in late stage development but their clinical efficacy in combination with endocrine therapy has been limited almost certainly by the inability to target them to identified resistance mechanisms. The newly founded Endocrinology Team, which was developed by the joining of the Translational Research Team (Mitch Dowsett) and the Molecular Endocrinology Team (Mitch Dowsett & Lesley-Ann Martin) to form a concerted effort, to generate increased knowledge on the important mechanisms of response and resistance specifically to oestrogen deprivation and most particularly to AIs by making use of large clinical data sets and in vitro laboratory models for hypothesis driven study.

Figure 1. Potential course of therapy for a postmenopausal woman with ER+ breast cancer who has relapsed on endocrine therapy.