Copper, Genes, and Cancer
By Dr. Kevin Conners
Recent literature is pointing to a correlation of higher tissue levels of copper in some cancers. Since some cancers can feed off of copper, as the element is necessary for rapid replication, speculation lends towards reducing copper levels as a possible intervention for cancer patients.
Copper is an essential nutrient for many cellular functions. However, studies have shown that nearly every cancer up-regulates copper and can use it to promote further growth. When measured, many cancer patients have elevated serum copper levels and a higher copper to zinc ratio than normal control. This contributes to tumor burden, advances the disease, and decreases survival rates. Some chemotherapy regimens add copper, knowing that cancers draw on it for continued replication and therefore may drag the chemotherapy with it to help kill the cancer cells.
It has been shown that copper levels may raise during active disease and fall in states of remission. Depleting copper levels may also decrease circulating tumor cells and help in stabilizing the replication rate. Environmental factors that may increase human exposure to copper include: copper consumed in supplements, copper in drinking water both from natural occurrence from soil and from copper pipes in household plumbing, copper cookware, and others. Individuals who are estrogen dominant, zinc deficient, and have adrenal insufficiency may also be at higher risk of exhibiting excess copper (6-15).
There are certain genes that regulate copper’s absorption and access to a cell. The SLC1 gene encodes for a protein found in the cell membrane that enables copper’s transportation in and out of a cell. Studies suggest that homozygous defects on this gene leaves excess copper in the extracellular matrix where, through a process known as the Fenton reaction, excess free radicals are generated which possibly damage cells and gobble up essential nutrients like selenium and zinc. All this is very important for the cancer patient because free radicals are a major cause of cancer, and zinc and selenium deficiencies are common in most cancers.
A study evaluated serum zinc, copper, and the Cu/Zn ratio in 84 patients with pulmonary lesions before surgery and in 100 healthy normal controls (1). There were 20 patients with benign and 64 with malignant lung tumors. The mean Cu/Zn ratio was significantly higher in malignant tumors (2.24 ± 0.78) than in benign tissue (1.63 ± 033). In the normal group, the Cu/Zn ratio was significantly lower (1.43 ± 0.29). Patients with advanced disease (Stage III or higher) had higher Cu/Zn ratio than patients in Stages I and II (2.65 ± 0.86 versus 1.9 ± 0.27). These findings suggest that Cu/Zn ratio may be used as a diagnostic test in cancer patients as it appears that, at least in some cancers, copper levels are up-regulated and zinc levels down-regulated.
The ATOX1 gene encodes for a copper chaperone that plays a role in copper homeostasis by binding and transporting cytosolic (within the cell) copper to ATPase proteins in the trans-Golgi network for later incorporation to the ceruloplasmin (the major copper transporter in the blood). (2) This protein also functions as an antioxidant against superoxide (a dangerous free radical) and hydrogen peroxide, and therefore, defects in this gene may play a significant role in cancer carcinogenesis. ATOX1 defects may lead to excess copper levels in the blood and may be associated with a greater efficacy of blood-born cancers such as leukemia and myeloma.
The copper efflux transporter ATP7A gene encodes for a protein to enable copper absorption and is overexpressed in some cisplatin-resistant ovarian carcinoma cell lines. One study (3) showed that ATP7A was expressed in some of the most common human malignancies, including prostate (7 of 7), breast (10 of 10), lung (8 of 8), colon (5 of 8), and ovary (6 of 7), as well as in a wide variety of other types of malignancy suggesting that cancer cells may become dependent on increased copper for survival.
Another study revealed ATP7A staining was detected in 28 of 54 ovarian carcinomas meaning that increased gene activity was present and patients with increased ATP7A expression exhibited poorer actuarial survival. Although ATP7A is not detectable in most normal tissues it is expressed in a considerable number of common tumor types.
Similarly, the ATP7B gene provides instructions for making a protein called copper- transporting ATPase 2. This protein is part of the P-type ATPase family, a group of proteins that transport metals into and out of cells by using energy stored in the molecule adenosine triphosphate (ATP). ATP7B was found to be overexpressed in human gastric carcinomas as well as other cancers including breast (4). Therefore, increased expression of ATP7 genes has been found to trap copper inside cancer cells allowing some cancers to ‘feed’ and increase the replication rate.
The CP gene encodes for the main copper transport protein in the blood, ceruloplasmin. It is suggested to have a role in cancer since it is involved in angiogenesis (creation of new blood vessels) and neovascularization (new vessels feeding a growing cancer), two essential components for continued growth and metastasis in cancer.
In order to understand the role of ceruloplasmin in malignant cells, one study isolated and sequenced a human ceruloplasmin cDNA clone. They investigated the ceruloplasmin gene expression in human colon and breast cancer cell lines. The poly (A)+ RNA from human colon (WiDr) and human breast (MCF-7) cancer cell lines was analyzed for the presence of ceruloplasmin mRNA. The Northern blot analysis revealed the presence of a 3.7 kb band of ceruloplasmin mRNA in these cell lines. Dot blot analysis revealed that ceruloplasmin mRNA is at least three fold more abundant in tumor cells as compared to normal rat liver cells. This data suggests that some cancers show a sharp increase in ceruloplasmin and copper activity.
The study also revealed that both copper and ceruloplasmin levels were increased significantly in the cancer patients as compared to controls (5). Serum copper and ceruloplasmin levels are known to increase in several malignancies such as osteosarcomas, some gastrointestinal tumors, and lung cancer. A study on primary brain cancer revealed serum copper and ceruloplasmin levels in 40 patients concluding that copper and ceruloplasmin represent a good complement to some other nonspecific parameters in evaluating the activity of malignancy and the therapeutic results since rises in copper and ceruloplasmin directly relate to increased growth.
While I understand that the above is quite technical and admittedly boring, extrapolation of useful clinical information may help many cancer patients.
Given the aforementioned data on copper, the question both patient and practitioner may want to ask is this: Could clinical intervention to help decrease copper levels in cancer patients increase survival outcomes? I believe that, though continued research may be necessary, reducing copper levels in cancer patients is important. This can be accomplished through chelation with homeopathy or other chelating agents, novel use of off-label medications that reduce copper levels, and wise use of nutrients like zinc and selenium whose levels appear to have an inverse relationship with copper.
In our practice we test for copper levels and since we began doing so, we’ve been astonished to find that most cancer patients benefit from using nutrients to reduce copper levels. We have found that homeopathic dosing works best and believe that it has improved outcomes. We have also coupled this with increasing selenium and zinc levels through both oral and topical applications.
Cancer has a notorious appetite and its use of copper, iron, glutamine, methionine, glucose, lactic acid, and other metabolites as a fuel source need continued research. However, I believe there is ample data to suggest novel approaches to reduce such fuel sources and help tumor burden in many patients.
Please contact Dr. Conners at Conners Clinic by visiting the website at www.ConnersClinic.com or calling 651.739.1248.
(1) Díez, M., Cerdà, F. J., Arroyo, M. and Balibrea, J. L. (1989), Use of the copper/zinc ratio in the diagnosis of lung cancer. Cancer, 63: 726–730. doi:10.1002/1097-0142(19890215)63:4<726::AID-CNCR2820630421>3.0.CO;2-P
(2) Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation
S Itoh, HW Kim, O Nakagawa, K Ozumi… – Journal of Biological …, 2008 – ASBMB
(3) Samimi, G., Varki, N.M., Wilczynski, S., Safaei, R., Alberts, D.S. and Howell, S.B., 2003. Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clinical cancer research, 9(16), pp.5853-5859.
(4) Kanzaki, A., Toi, M., Neamati, N., Miyashita, H., Oubu, M., Nakayama, K., Bando, H., Ogawa, K., Mutoh, M., Mori, S. and Terada, K., 2002. Copper‐transporting P‐type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma. Cancer Science, 93(1), pp.70-77.
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