What is tamoxifen?
Even though it was known that certain cancers respond to estrogen with growth and increased survival, a clinical trial to explore tamoxifen’s activity in advanced breast cancer was not done until 1971. Since the results were very promising, ICI pharmaceuticals, the company who had first synthesized the drug in 1962, followed up with several new clinical trials for breast cancer. It was approved for the use in advance breast cancer in the United Kingdom in 1973, followed by its approval in the United States in 1977.
In the 1980s, several clinical trial were published that showed a major effect of tamoxifen in early breast cancer especially when given as an adjunct therapy together with surgery or radiation therapy. Since it has a relatively mild side effects like hot flashes, dryness in the vagina, an increased risk for blood clots and other menopausal type symptoms, it is now also used in women who are still healthy, but have a high risk to develop breast cancer because of mutations in certain genes (“breast cancer genes” like e.g. BRCA1 and BRCA2) to prevent the development of breast cancer. In women with early breast cancer it can prevent the formation metastases, it can stop the growth of the original tumor and thus prevent its re-growth and it can also inhibit the development of new tumors in the other breast.
How does tamoxifen fight breast cancer?
Tamoxifen is an inhibitor of the female hormone estrogen. Healthy mammary gland tissue and many breast cancers have a protein on their cell surface that is called the estrogen receptor. This protein can bind the hormone estrogen. The binding of the hormone gives the cell a powerful stimulus that can make the cell grow and can also induce changes in the cell that can enable the cell to better survive stressful situation like e.g. when the cell is bombarded with radiation or other cancer drugs.
Tamoxifen inhibits the binding of estrogen to its receptor by binding in its place. However, tamoxifen cannot induce the signals that the binding of the estrogen to the receptor induces. It therefore inhibits the actions of estrogen much like if a key that can fit in a lock, but does not open the lock, is broken in it. The real key that can turn the lock is now useless, as it will no longer be able to fit into the lock. Since tamoxifen does this in all cells of the body that have the estrogen receptor on their surface, tamoxifen can cause side effects similar to the hormonal changes that are associated with menopause. Sometimes bodybuilders who abuse steroids also abuse tamoxifen, as it can increase the efficacy of steroids.
Why does tamoxifen fail to work for certain breast cancers?
There are several different reasons why tamoxifen fails to work for certain breast cancers. Some cancers are never sensitive to it, and others develop resistance over time. Researchers are now starting to understand the reasons behind this.
Not all breast cancers express the estrogen receptor on their cell surface. These types of cancers which, in contrast to the estrogen-depended ones that are called hormone sensitive and that respond well to treatment with tamoxifen, are called hormone insensitive and do not respond to treatment with tamoxifen at all. Before the start of a treatment regimen with tamoxifen, the physician will therefore determine first whether this specific case of breast cancer is of the hormone sensitive or insensitive kind.
After taking tamoxifen, the drug needs to go to the liver, where it is converted into its active form, before it can do its job in the breast cancer cells. Some people have mutations in the genes for the machinery in the liver that does this conversion process. Tamoxifen’s activity will be greatly reduced in these people, so that these people either need to take a higher dose and risk more side effects, or in more severe cases, Tamoxifen might not work at all. Genetic tests can be done to determine before the start of the treatment whether somebody has these mutations.
Sometimes the cancer cells change over time, and tumors that used to be sensitive to tamoxifen, suddenly don’t respond anymore. A recent study done by researchers at the Institute of Cancer Research’s (ICR) Breakthrough Breast Cancer Research Centre in London shows a new mechanism, how cancer cells can develop this resistance to tamoxifen.
Tamoxifen shuts down the signaling pathway of the hormone estrogen on breast cancer cells. Estrogen acts as a so-called growth factor on the cells, which means it’s a hormone that tells a cell to grow and induces changes in the cells that help them survive. Healthy cells in the body will die automatically, if they do not receive signals from growth factors regularly. Cancer cells often don’t die under these conditions, but they still will survive and grow better, in the presence of growth factors.
In biological systems, it is very common that an important function can be taken over by another similar system at least in part as an insurance policy in the case that something goes wrong with the primary system. This is especially true for growth factors that signal cells to grow and help them to survive stressful situations. There are many different growth factors that provide similar stimuli for the cell that have receptors for them on their cell surface. They are named by the kind of cell that produces them and sometimes additionally the kind of tissue that usually responds to them e.g. VEGF stand for vascular epithelial growth factor as it is a growth factor produced in the vasculature that acts on epithelial cells.
20 slightly different fibroblast growth factors known today
A very common growth factor that is truly an entire family of slightly different growth factors that all have very similar functions, is the family of FGF, which stands for fibroblast growth factor. There are more than 20 slightly different fibroblast growth factors known today. Fibroblast growth factors can induce cell growth and survival in a number of different tissues and they have an important role in the body. Lack of certain FGF’s can lead to conditions like e.g. an increased susceptibility for diabetes.
In cancerous tissue however, they can make cells less sensitive to certain cancer drugs and increase growth of the tumor. The recent study reported in the journal Cancer by the Institute of Cancer Research’s (ICR) Breakthrough Breast Cancer Research Centre in London showed that breast cancers that are resistant to tamoxifen treatment despite the fact that they express the estrogen receptor, often have multiple copies of an FGF-receptor called FGFR1. This enables the cells to produce much more of this receptor than healthy cells. The cells become hypersensitive to the actions of FGF’s, so that they need very little FGF to be able to survive. In the presence of FGF’s these cells no longer need to rely on estrogen for survival and growth, and thus tamoxifen is useless in the fight against these cancer cells.
Some cancer cells employed an even more deviant way to become independent of the estrogen survival signal. They acquired a mutation in the FGFR1 that enables this receptor to give the growth and survival signal even in the absence of the growth factor. Cancers that have this kind of short circuit in their signaling pathways are very hard to treat with chemotherapy of any kind and have a very poor prognosis.