Copper is a vital nutrient required for normal iron metabolism and blood cell formation. Women with low iron stores are at risk of anemia if they do not have adequate copper intake. However, excess levels of copper have been linked to higher risk of breast cancer and its progression. In fact, tumor tissue concentrations of copper tend to be elevated in breast cancer patients and can be very high.
Now a new study has reported on a novel copper chelator which can inhibit tumor growth and significantly extend survival in mice bearing triple negative (ER-/PR-/HER2-) tumors.
Copper promotes breast cancer
Copper has been shown to promote angiogenesis (new blood vessel formation) in existing breast tumors, as well as to facilitate breast cancer cell migration and invasion. Copper also appears to have a role in evasion of the immune system by cancer cells. It has been demonstrated that careful manipulation of copper levels in tumor cells can alter intracellular processes to favor the induction of apoptosis (programmed cell death). In fact, reducing available copper appears to affect multiple facets of the tumor microenvironment, resulting in an inhospitable setting for tumor progression.
Substantially lowering copper levels in breast cancer patients at high risk for recurrence using a copper chelator (a drug designed to lower circulating copper) also appears to promote tumor dormancy and help prevent relapse. Inducing copper deficiency has been shown to reduce tumor development and angiogenesis in mouse models of HER2 overexpressing (HER2+) and inflammatory breast cancer (IBC).
Food sources of copper
The following foods have high concentrations of copper:
Calf's liver contains 12 to 15 mg of copper per 100 g (3.5 oz.), which is well above the recommended dietary allowance (RDA) of 0.9 mg per day. On the other hand, the copper content of chicken liver is only about 0.5 mg per 100 g. The foods below contain far less copper than calf's liver, but are potentially significant sources of copper, depending on the frequency and volume of consumption:
- Basil pesto
- Chocolate & cocoa powder
- Nuts, especially Brazil nuts, cashews, hazelnuts, pine nuts, pistachio nuts & walnuts,
- Pumpkin seeds
- Sesame seeds & sesame oil
- Shellfish, especially oysters, squid & lobster
- Products made from defatted soy flour, e.g., soy protein isolate & textured soy protein
- Sun dried tomatoes
- Sunflower seeds
Most nuts are a significant source of copper. However, walnuts have significant chemopreventive properties and should be consumed in moderation rather than avoided because of its copper content. The copper content of most common foods can be found at SELFNutritionData. Note that curcumin, the most biologically active ingredient in turmeric, has been shown to act as a copper chelator.
Other sources of copper exposure
U.S. residents typically consume more than enough copper. In fact, copper deficiency is rare. Despite this, most multivitamins, including those for women and seniors, contain copper. Copper cookware and copper jewelry (including red, rose or pink gold) are other potential sources of copper exposure. It has been demonstrated that copper bracelets can deliver copper through the skin. Soldering or otherwise working with copper can also result in exposure. In addition, living near copper mining or smelting operations can result in inhalation of airborne dust containing copper.
Latest research describes copper chelator effective in TN disease
The study referenced above describes a new type of copper chelator and evaluates its effectiveness against triple negative breast cancer. Existing copper chelators are "too toxic or ineffective for cancer treatment," according to the authors. This motivated them to develop a copper-depleting nanoparticle that targets the mitochondria (the organelles which generate the bulk of cellular energy through adenosine triphosphate (ATP) production). Depriving mitochondria of copper, thereby reducing ATP production, has been shown to be effective against some cancer types. The authors predicted that the copper-depleting nanoparticles would be less toxic than currently available copper chelators since the nanoparticles target mitochondrial copper levels rather than inducing systemic copper deprivation.
In the study, after developing the copper-depleting nanoparticles, the authors first tested them against triple negative breast cancer cells. The nanoparticles caused an anticipated metabolic switch which reduced ATP production in the mitochondria. The resulting energy deficiency, which was accompanied by compromised mitochondrial membrane potential and increased oxidative stress, resulted in apoptosis. The authors then demonstrated that the copper-depleting nanoparticles had low toxicity in healthy mice. Finally, the authors tested the effectiveness of the nanoparticles in three mouse models of triple negative breast cancer. Administration of the nanoparticles was shown to inhibit tumor growth, as well as to significantly extend survival of the mice. The authors conclude that the demonstrated safety and effectiveness of the newly-developed copper-depleting nanoparticles suggest the potential for development of clinical treatment based on this approach.
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Selected breast cancer studies
Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Voli F, Valli E, Lerra L, Kimpton K, Saletta F, Giorgi FM, et al. Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion. Cancer Research. American Association for Cancer Research (AACR); 2020; 80:4129-4144 10.1158/0008-5472.can-20-0471
Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration
Blockhuys S, Zhang X, Wittung-Stafshede P. Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration. Proceedings of the National Academy of Sciences. Proceedings of the National Academy of Sciences; 2020; 117:2014-2019 10.1073/pnas.1910722117
Bioaccumulation of trace metals in farmed pacific oysters Crassostrea gigas from SW Gulf of California coast, Mexico
Jonathan M, Muñoz-Sevilla N, Góngora-Gómez AM, Luna Varela RG, Sujitha S, Escobedo-Urías D, et al. Bioaccumulation of trace metals in farmed pacific oysters Crassostrea gigas from SW Gulf of California coast, Mexico. Chemosphere. Elsevier BV; 2017; 187:311-319 10.1016/j.chemosphere.2017.08.098
Abstract LB-349: Copper depletion as a strategy to affect the tumor microenvironment in breast cancer patients at high risk of relapse and in triple negative preclinical models of breast cancer: Updated results of a phase II study of tetrathiomolybdate (TM) in breast cancer (BC) patients (pts) at high risk for recurrence
Nackos E, Lee S, Willis A, Kornhauser N, Ward M, Cobham M, et al. Abstract LB-349: Copper depletion as a strategy to affect the tumor microenvironment in breast cancer patients at high risk of relapse and in triple negative preclinical models of breast cancer: Updated results of a phase II study of tetrathiomolybdate (TM) in breast cancer (BC) patients (pts) at high risk for recurrence. Tumor Biology. American Association for Cancer Research; 2016; 10.1158/1538-7445.am2016-lb-349
Detention of copper by sulfur nanoparticles inhibits the proliferation of A375 malignant melanoma and MCF-7 breast cancer cells
Liu H, Zhang Y, Zheng S, Weng Z, Ma J, Li Y, et al. Detention of copper by sulfur nanoparticles inhibits the proliferation of A375 malignant melanoma and MCF-7 breast cancer cells. Biochemical and Biophysical Research Communications. Elsevier BV; 2016; 477:1031-1037 10.1016/j.bbrc.2016.07.026
Curcumin is a biologically active copper chelator with antitumor activity
Zhang W, Chen C, Shi H, Yang M, Liu Y, Ji P, et al. Curcumin is a biologically active copper chelator with antitumor activity. Phytomedicine. Elsevier BV; 2016; 23:1-8 10.1016/j.phymed.2015.11.005
Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation
Wang J, Luo C, Shan C, You Q, Lu J, Elf S, et al. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. Nature Chemistry. Springer Science and Business Media LLC; 2015; 7:968-979 10.1038/nchem.2381
Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism
Sarwar T, Zafaryab M, Husain MA, Ishqi HM, Rehman SU, Moshahid Alam Rizvi M, et al. Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism. Toxicology and Applied Pharmacology. Elsevier BV; 2015; 289:251-261 10.1016/j.taap.2015.09.018
Dietary Supplements and Mortality Rate in Older Women
Mursu J. Dietary Supplements and Mortality Rate in Older Women. Archives of Internal Medicine. American Medical Association (AMA); 2011; 171:1625 10.1001/archinternmed.2011.445