Breast cancer is one of the commonest cancers, now affecting about 1 in 8 women. However, early detection and good treatments mean that survival rates have increased to about 80%. Animal studies led to the development of tamoxifen, one of the most successful treatments, and more recently Herceptin (trastuzumab) and aromatase inhibitors.
Normal breast development is controlled by hormones, including oestrogens and progesterone. These hormones and their roles fertility and development were discovered during the 1930s through fundamental research on animals. Evidence for their role in the development of some cancers came about through animal studies in the 1950s, when researchers discovered that hormone changes can induce breast tumours in rats. Tamoxifen emerged from a research programme aimed at the development of an anti-oestrogen oral contraceptive. However tamoxifen proved much more interesting both as a treatment and then as a preventative measure in breast cancer. It was licensed for use in the mid 1970s and became one of the most successful breast cancer medicines.
An analysis in 2000 showed that there was an unprecedented fall of about 30% in the death rate from breast cancer in the UK in the 1990s. This improvement is due in part to use of tamoxifen, which was then in widespread use in the UK - earlier than in the USA or other European countries.
The suggestion that tamoxifen can prevent the development of breast cancer in healthy women who have a family history of the disease came from research on rats and mice.1 The study showed that tamoxifen provided long-lasting protection against breast cancer and many other cancers. When given tamoxifen from an early age for life it increases the rats' risk of liver cancer, but does not increase the risk when given at an older age, which is more applicable to most human patients.
Tamoxifen has different effects in different species and between different tissues in the body, either increasing or decreasing the effects of oestrogen. It is its role in reducing oestrogen in breast tissue that makes it effective, but the pro-oestrogen activity in other tissues result in side-effects.2
Tamoxifen has also been used to develop alternatives to using animals in breast cancer research, by proving that human tumour cells grown in laboratory cell cutures will respond to the same drugs that work in patients. Without the animal work, it would have been difficult if not impossible to demonstrate that the cell culture results were relevant and reliable.
Aromatase inhibitors block production of the oestrogen, ‘starving’ breast cancer cells of growth stimuli. Professor Angela Brodie of the University of Maryland School of Medicine developed the aromatase inhibitors3 and tested them in mice, comparing them with tamoxifen, then the gold-standard treatment for ‘oestrogen-receptor-positive’ cancers.
This research showed how animal models can predict patient response not just to a particular medicine, but to different combinations of therapy – a critical factor in cancer treatment. For example, animal studies with combinations of tamoxifen and aromatase inhibitors did not show any improvement over established treatments.
Aromatase inhibitor therapy alone was shown to be the most effective4, and after clinical trials aromatase inhibitors were approved for use in patients with oestrogen-fuelled breast cancer. Later studies with patients showed that sequential treatment with tamoxifen and then the aromatase inhibitor exemestane improved survival rates for this type of breast cancer, and could save a further 1,300 lives a year in the
The development of Herceptin was another a landmark in breast cancer research. In 2005, researchers reported a 50% fall in the rate of breast cancer recurrence after one year of treatment.6 This degree of benefit in early breast cancer was the largest reported since the introduction of tamoxifen.
Herceptin only seems to work when breast cancer cells over-express a protein known as HER-2 which normally helps to regulate cell growth. Over-expression of HER-2 occurs in 20% to 30% of breast tumours. HER-2 was discovered in 1979 in neurological tumours of rats at the Massachusetts Institute of Technology.7 It took nearly 20 years to develop Herceptin, a monoclonal antibody that targets HER-2.
Animal studies also highlight possible risks associated with new drugs in specific groups of patients. For example, Herceptin is not routinely recommended for nursing mothers after studies showed that monkeys secrete it in milk.8
4. Schuetz K (2004) See Translating Basic Research into Patient Care: An Interview with Dr. Angela Brodie http://www.umgcc.org/news/brodie_home.htm (accessed 16 February 2007).