Inhibiting Breast Cancer Recurrence through Copper Reduction using Repurposed Tetrathiomolybdate

In 2013 a research paper was published that reported a dramatic decrease in recurrence rates for women with triple negative breast cancer (aka. TNBC). The study used a repurposed medication known as tetrathiomolybdate to lower copper levels in women with a history of TNBC. At the end of one year, 85% of the women remained disease-free. This was a fantastic result, as typically 30-40% of women with TNBC experience a recurrence.

So why would copper influence breast cancer recurrence? Copper is an essential mineral, with most women requiring about 900mcg per day. Pregnancy and lactation can increase the daily need a bit, but even with that copper deficiency is pretty rare. In medicine, copper levels are assessed by measuring a protein called ceruloplasmin. Roughly 90% of circulating copper is held by ceruloplasmin, making it a pretty good indicator of a person's copper levels. Copper has many very important functions in the body: immune function, energy production, and brain health, among others. However, in cancer it seems that one of copper's functions, stimulation of angiogenesis, can be hijacked.

Angiogenesis is a term used to describe the production of new blood vessels. For example, if the arteries in someone's heart become clogged with cholesterol plaques, the flow of blood can be diminished. Think of the plaque like a dam on a river; it holds back the flow. The heart muscle on the downstream side of dam starts receiving less blood and the oxygen and nutrients it carries. This reduction in oxygen and nutrients inhibits the heart from properly doing it's job, and this is how a heart attack happens. Thankfully, those cholesterol plaques don't typically build up super quickly; it happens over time. As the plaques get larger and larger the downstream tissue starts receiving less and less oxygen and nutrients. In response to the diminishing resources the downstream tissue will start sending out an SOS signal, "Tissue in distress. Low oxygen. Help!" This SOS signal is vascular endothelial growth factor (VEGF). The distressed tissue emits the VEGF which then disperses into the nearby tissues. When the VEGF is sensed by an artery, the artery will respond by growing a branch towards the distressed tissue. When the new arterial branch reaches the source of the VEGF, it plugs in creating a collateral circulation that then delivers the needed oxygen and nutrients, essentially saving the day. This is a great mechanism for preventing a heart attack.

Cancer cells can also become nutrient-starved. As cancer cells are mutated versions of normal cells, they retain many of the normal cell abilities, like producing VEGF. The blood vessels in the body can't differentiate VEGF from a cancer cell versus VEGF from a normal cell. They only sense VEGF and think "tissue in distress- must help!" Not knowing the tissue they are about to perfuse with nutrients are cancer cells. Not a good thing.

Many, if not all cancers require new blood vessel formation for their continued growth and survival. In fact, it is now recognized that elevated ceruloplasmin levels can be a negative prognostic marker for breast cancer recurrence, ie. the higher a woman's ceruloplasmin level, the higher her risk of recurrence.

Copper, as it turns out, is intimately involved in the production of VEGF. In response to low oxygen content within the impacted tissue a transcription factor called HIF-alpha is produced. HIF-alpha then stimulates the production of VEGF, when is then secreted into the tissues.

The 2013 study found that when a woman's ceruloplasmin level was decreased to a therapeutic level, and then maintained there, the risk of recurrence was significantly decreased. Tetrathiomolybdate (TM) is a repurposed drug, it has traditionally used to treat Wilson's disease, an inherited copper storage condition. When used at appropriate dosages TM is safe and well tolerated by most. It is a sulfur-containing compound, so some people may experience the occasional sulfur-flavored burp. However, using TM is not without some risk, making it very important to be treated and monitored by a physician experienced with this medication.

If copper levels are depleted too low, bone marrow suppression may occur resulting in lowered blood cell counts. This means that if a person's copper level is reduced too low then the body will have difficulty making red and white blood cells, possibly causing anemia and impairing the immune system. However, this is quickly reversed by restoring adequate copper levels.

Again, it is essential to be be monitored by a physician who can regularly monitor blood copper levels.

The potential of TM to lower blood counts can make using tetrathiomolybdate along with conventional therapies tricky, as these therapies often also cause decreased blood cell counts. However, it has now been shown that adding TM to conventional care can help to prevent treatment resistance, ie. chemo-resistance, in a number of cancers including breast cancer, ovarian cancer,and lung cancer.

As an anti-cancer therapy tetrathiomolybdate shows much promise, especially in the prevention of triple negative breast cancer. When used as part of a integrated cancer treatment plan TM is safe, well tolerated, and can reduce the risk of recurrent disease.

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