Exposure to cadmium reduces effectiveness of tamoxifen
|Environmental exposure to cadmium in breast cancer — association with the Warburg effect and sensitivity to tamoxifen Cite
Tarhonska K, Janasik B, Roszak J, Kowalczyk K, Lesicka M, Reszka E, et al. Environmental exposure to cadmium in breast cancer – association with the Warburg effect and sensitivity to tamoxifen. Biomedicine & Pharmacotherapy. Elsevier BV; 2023; 161:114435 10.1016/j.biopha.2023.114435
|Biomedicine & Pharmacotherapy, May 2023|
Cadmium reduces tamoxifen effectiveness
Cadmium is an estrogenic heavy metal (a metalloestrogen) with no beneficial effects on health. It functions as an endocrine disruptor, stimulating estrogen receptor (ER) activity. Since the body does not readily eliminate it, cadmium accumulates in tissues. Cadmium exposure has been linked to increased breast cancer risk.
Breast cancer patients tend to have higher levels of cadmium in their breast tissue than cancer-free women. Cadmium is associated with increased breast density, a strong breast cancer risk factor. Cadmium has been shown to promote uterine and mammary gland growth in mice. Numerous studies have demonstrated that cadmium increases the growth and proliferation of breast cancer cells. Cadmium exposure has also been linked to increased risk of breast cancer in epidemiological studies, although not all studies have reported an association.
Cadmium has been shown to interfere with the treatment effects of aromatase inhibitors and 5-fluorouracil (5-FU) chemotherapy in hormone receptor positive (ER+/PR+) breast cancer cells. Now a new study has reported that cadmium also appears to reduce the effectiveness of tamoxifen treatment.
Non-dietary sources of cadmium exposure
Cadmium is easily absorbed through the lungs, less easily absorbed in the digestive tract, and difficult to absorb through the skin. Cadmium is released into the environment from numerous types of mining, metal smelting, manufacturing and waste disposal operations. People living near or working for such industries might be exposed to relatively high levels of cadmium in the air. Cadmium is also found in vehicle exhaust, leading to potentially high levels of cadmium in soils near roads. Cigarettes are also a possible source of significant cadmium exposure.
Dietary sources of cadmium
Diet is the primary source of cadmium exposure for most U.S. women. Both developed and less developed countries have problems with cadmium contamination of coastal waters, leading to potentially high levels in shellfish. In addition, there are large areas of some countries, including the U.S., Canada and China, in which significant levels of cadmium are found naturally in the soil. Certain plants take up and incorporate cadmium more readily than others. Included are rice and other cereal grains, flaxseed, potatoes, sunflowers, peanuts, spinach and other leafy vegetables, and tobacco. Generally speaking, cooking is not effective in reducing cadmium concentrations in food.
Most U.S. women can limit their cadmium exposure by avoiding all but modest consumption of the following foods:
- Dark chocolate
- Flaxseed produced in high-cadmium regions
- Sunflower seeds
- Rice produced in Louisiana, Thailand or India
- Dried apricots from Turkey
- Free range escargot snails
- Indian mustard (black mustard) imported from the old Soviet Union, India or China.
If one of the foods you enjoy is on the list above, make every attempt to find a low-cadmium source. Those growing their own vegetables should avoid using roadside plots. Please see our article on cadmium for more detailed information concerning sources of exposure.
Latest research finds cadmium interferes with tamoxifen
The study referenced above was designed to investigate the relationship between environmental exposure to cadmium and the Warburg effect in breast cancer, thereby explaining cadmium's possible interference with breast cancer treatment. The authors also examined the influence of cadmium on treatment with tamoxifen.
The Warburg effect is a form of deviant energetic metabolism whereby the rate of glucose uptake is significantly increased. Together with activation of key proliferative and survival signaling pathways, the Warburg effect plays a critical role in tumorigenesis, suggesting that compounds targeting key proteins involved in the Warburg effect could act as cancer treatment.
The authors performed an observational study, using two groups of breast cancer patients, which found a link between urinary cadmium levels and tumor expression of HIF1A (a key regulator of the Warburg effect). However, further studies using ER+/PR+ MCF-7 breast cancer cells failed to confirm that cadmium exposure had an influence on molecular and biochemical markers of the Warburg effect.
On the other hand, long-term exposure to a low and environmentally relevant concentration of cadmium led to its accumulation in ER+/PR+ cells and reduced their sensitivity to tamoxifen. The authors conclude that an association between cadmium and the Warburg effect was suggested in their observational study, while not confirmed in cell studies. However cadmium appears to interfere with tamoxifen treatment, a finding which deserves further study since it implies resistance to hormone therapy.
Please see our articles on tamoxifen and cadmium and breast cancer for more information.
Selected breast cancer studies
Dietary intake of household cadmium-contaminated rice caused genome-wide DNA methylation changes on gene/hubs related to metabolic disorders and cancers
Zhang S, Xie W, Zhai Z, Chen C, Zhao F, Wang P. Dietary intake of household cadmium-contaminated rice caused genome-wide DNA methylation changes on gene/hubs related to metabolic disorders and cancers. Environmental Pollution. Elsevier BV; 2023;:121553 10.1016/j.envpol.2023.121553
Exposure to environmental chemicals and cancer risk: epidemiological evidence from Japanese studies
Iwasaki M, Itoh H, Sawada N, Tsugane S. Exposure to environmental chemicals and cancer risk: epidemiological evidence from Japanese studies. Genes and Environment. Springer Science and Business Media LLC; 2023; 45 10.1186/s41021-023-00268-3
The Effect of Metalloestrogens on the Effectiveness of Aromatase Inhibitors in a Hormone-Dependent Breast Cancer Cell Model
Boszkiewicz K, Moreira H, Sawicka E, Szyjka A, Piwowar A. The Effect of Metalloestrogens on the Effectiveness of Aromatase Inhibitors in a Hormone-Dependent Breast Cancer Cell Model. Cancers. MDPI AG; 2023; 15:457 10.3390/cancers15020457
miR-3614–5p downregulation promotes cadmium-induced breast cancer cell proliferation and metastasis by targeting TXNRD1
Yue Y, Tan M, Luo Y, Deng P, Wang H, Li J, et al. miR-3614–5p downregulation promotes cadmium-induced breast cancer cell proliferation and metastasis by targeting TXNRD1. Ecotoxicology and Environmental Safety. Elsevier BV; 2022; 247:114270 10.1016/j.ecoenv.2022.114270
Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis
Zhao L, Islam R, Wang Y, Zhang X, Liu L. Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis. Cancers. MDPI AG; 2022; 14:5768 10.3390/cancers14235768
Cadmium: A Focus on the Brown Crab (Cancer pagurus) Industry and Potential Human Health Risks
Lordan R, Zabetakis I. Cadmium: A Focus on the Brown Crab (Cancer pagurus) Industry and Potential Human Health Risks. Toxics. MDPI AG; 2022; 10:591 10.3390/toxics10100591
Cadmium tissue level in women diagnosed with breast cancer – A case control study
Anđelković M, Djordjevic AB, Miljaković EA, Javorac D, Čolaković N, Oprić S, et al. Cadmium tissue level in women diagnosed with breast cancer – A case control study. Environmental Research. Elsevier BV; 2021;:111300 10.1016/j.envres.2021.111300
Exposure to lead and cadmium of the Belgian consumers from ceramic food contact articles
Li Y, Zhang J. Exposure to lead and cadmium of the Belgian consumers from ceramic food contact articles. Toxicology Reports. Elsevier BV; 2021; 10.1016/j.toxrep.2021.02.015
Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor– positive breast cancer cells
Sun X, Fontaine J, Bartl I, Behnam B, Welsh MJ, Benndorf R. Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor– positive breast cancer cells. Cell Stress & Chaperones. Springer Science and Business Media LLC; 2007; 12:307 10.1379/csc-276.1