Re: TOXIC METALS & BREAST CANCER:NEW RESEARCH & DEVELOPMENT

January 13, 2008

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> Toxic Metals and Breast Cancer: New Research and Development

> by E.Blaurock-Busch, PhD

> http://www.townsendletter.com/AugSept2007/toxicmetalbreastcancer0807.htm

>

> General Information and Statistics

> According to the most recent statistics provided by the National Cancer

> Institute, breast cancer is (aside from non-melanoma skin cancer) the number

one

> cause of cancer-related deaths in Hispanic women. It is the second most

> common cause of cancer death in white, black, Asian/Pacific Islander, and

American

> Indian/Alaska Native women.

>

> In 2003 (the most recent numbers available), statistics revealed the

> following:

> 181,646 women and 1,826 men were diagnosed with breast cancer.*

> 41,619 women and 379 men died from breast cancer.* In comparison, Figure 1

> shows how breast cancer compares to other common causes of death in American

> women of all ages.

>

> Figure 1: Causes of Death in American Women (2003)

> *Note: Incidence counts cover approximately 96% of the U.S. population and

> death counts cover 100% of the US population. Use caution in comparing

> incidence and death counts.

>

> Several risk factors have been found that may increase a woman's chances of

> developing breast cancer. These include the following:

> Getting older

> Early onset of menstrual period

> Starting menopause at a later age

> Being older at the birth of the first child

> Never giving birth

> Not breastfeeding

> Personal history of breast cancer or some non-cancerous breast diseases

> Family history of breast cancer (mother, sister, daughter)

> Treatment with radiation therapy to the breast/chest

> Being overweight (increases risk for breast cancer after menopause)

> Long-term use of hormone replacement therapy (estrogen and progesterone

> combined)

> Having changes in the breast cancer-related genes BRCA1 or BRCA2

> Using birth control pills, also called oral contraceptives

> Drinking alcohol (more than one drink a day)

> Not getting regular exercise

>

> Metals and Cancer

> Recent research indicated toxic metals, particularly cadmium, nickel, and

> aluminum as another cause of breast cancer. These heavy metals have been known

> to have specific effects on several biological systems. Dr. Maggie Louie,

> assistant professor in the Department of Natural Sciences and Mathematics,

> Dominican University of California, has received a $150,000 grant from the

> National Institutes of Health (NIH) in support of breast cancer research at

the

> University. Dr. Louie's work focuses on the potential role that environmental

> contaminants play in the development of breast cancer.

>

> Dr. Louie is studying how the heavy metal cadmium - an environmental

> contaminant that enters the body through consumption of contaminated food or

water,

> or inhalation of cigarette smoke - contributes to the development of breast

> cancer. Her preliminary findings not only show that cadmium promotes breast

> cancer cell growth, but her lab may have also identified a potential pathway

> for its action.

>

> Breast cancer results from the abnormal growth of cells in the mammary

> gland. The development of the mammary gland is regulated by estrogen, a

hormone

> that binds to the estrogen receptor (ER). Most breast cancer cases initially

> develop as hormone-dependent cancer, in which growth and progression of the

> disease correlates with estrogen levels. Doctors have been battling this

cancer

> with drugs known as anti-estrogens, which are designed to block the receptor.

> Although such treatments have proven successful, the cancer can later

> develop into a more aggressive, hormone-independent tumor.

>

> " The mechanism of how hormone independence develops is not clear, and my

> current research is focused on understanding the mechanism of how

> hormone-refractory breast cancer develops, " says Louie. " One potential

mechanism may

> involve endocrine disruptors including heavy metals such as cadmium. " Several

> studies conducted by researchers elsewhere back up the theory that cadmium may

> enhance the ER function and promote the development of breast cancer. Louie's

> preliminary findings show, however, that cadmium may also activate another

> signaling mechanism and promote breast cancer.

>

> Stoica and others documented that cadmium mimics the effects of estradiol in

> estrogen-responsive breast cancer cell lines. In addition, cadmium also

> blocks the binding of estradiol to ER-alpha in a noncompetitive manner. This

> suggests that cadmium may interact with the hormone-binding domain of the

> receptor. Treatment with cadmium resulted in a decrease in estrogen receptor,

> increased growth of MCF-7 cell lines, and increased levels of progesterone

> receptor, pS2, and cathepsin D. " Results from this study will not only provide

a

> better understanding of how environmental contaminants such as cadmium can

> promote breast cancer, but also offer new insights to how the estrogen

receptor can

> regulate both classical and non-classical ER target gene expression, " says

> Louie.

>

> Research Objective

> High levels of transition metals like iron, nickel, chromium, copper, and

> lead are closely related to free radical generation, lipid peroxidation,

> formation of DNA-strand breaks, and tumor growth in cellular systems. Reports

in

> the last two decades closely relate the presence of transition metals like

iron

> (Fe) or copper (Cu) to free radical generation via Fenton- and

> Haber-Weiss-reactions, ascorbate autoxidation, lipid peroxidation processes,

and formation

> of DNA strand breaks.2,12,14,19 In turn, lipid peroxidation-induced

> malondialdehyde-DNA adducts can accumulate and reach high levels in the breast

tissue

> of women with breast cancer leading to endogenous DNA modifications.24

> Furthermore, ferric-ethylendiamine N,N'-diacetate (EDDA), and nitrilotriacetic

> acid (NTA) complexes were shown to induce free radicals and renal carcinomas

in

> Wistar rats, demonstrating the key role of transition metals in the abnormal

> proliferation process.9,16 As repeated mitochondrial and nuclear DNA

> mutations may lead to malignant growth, we (Prof. G. Ionescu, PhD, Jan

Novotny,

> MD, Assoc. Prof. Vera Stejskal, PhD, Anette L?ch, PhD, Eleonore

> Blaurock-Busch, PhD, Marita Eisenmann-Klein, MD) investigated the accumulation

of 12 heavy

> metals in eight healthy and 20 breast cancer biopsies.

>

> Material and Methods

> Heavy metal analyses were performed on 20 frozen breast cancer biopsies and

> eight healthy breast tissue samples supplied by the Institute of

> Pathophysiology and Oncology, University, Prague, Czech Republic, and

the Caritas

> Hospital St. f, Regensburg, Germany.

>

> The concentrations of iron (Fe), cadmium (Cd), lead (Pb), chromium (Cr), tin

> (Sn), nickel (Ni), copper (Cu), mercury (Hg), silver (Ag), gold (Au),

> palladium (Pd), and zinc (Zn) in the biopsy material were measured in the

> Spezialklinik Neukirchen, Germany, by a standardized furnace-atomic absorption

> spectrohotometry (AAS)-technique using a Perkin Elmer Sima 6000

AA-spectrophotometer

> and acidic hydrolysis as pulping procedure for sample preparation.

>

> Additionally, heavy metal analysis in all control biopsies was done by using

> an inductive coupled plasma-mass spectroscopy (ICP-MS) with cell technique

> in the Laboratory for Micro Trace Minerals, Hersbruck, Germany. All tests were

> performed three times. The result per sample is the mean value of three

> determinations expressed in ?g/kg.

>

> Table 1

> Heavy metal content in breast cancer (n = 20) and healthy breast tissue (n =

> 8) biopsies (12KB .pdf)

>

> Results

> The Mann-Whitney U Test was used for statistical analysis of the results. A

> highly significant accumulation of iron (p < 0.0001), nickel (p < 0.00005),

> chromium (p < 0.00005), zinc (p < 0.00001), cadmium (p < 0.005), mercury (p <

> 0.005), and lead (p < 0.05) was recorded in the cancer samples when compared

> to the control group. Copper and silver showed no significant differences to

> the control group, whereas tin, gold, and palladium were not detectable in

> any biopsies. (See Table 1.) There was no statistical difference in the heavy

> metal content of the control biopsies when analyzed by AAS or ICP-MS (data not

> shown).

>

> Discussion

> In biological systems, the concentration of redox-active transition metals

> capable of catalyzing and/or generating free radicals like superoxide,

> hydrogen peroxide, and hydroxyl radical appears to be relatively low. However,

under

> certain pathological conditions (haemochromatosis, disease,

> collagenoses, and various malignancies), transition metals and their transport

> proteins may accumulate in different target organs inducing cellular lipid

> peroxidation and DNA-attack.

>

> In this respect, the ability of excess Fe in mediating the formation of

> hydroxyl radicals, suppressing cellular immune functions, and promoting tumor

> growth is well-established. Increased Cu concentrations were also found in

human

> lung cancer biopsies and in other tumors. Ni, Cr, and Cd have been

> recognized as mutagens and carcinogens through their ability to inhibit the

repair of

> damaged DNA. In addition, they can enhance the mutagenicity and

> carcinogenicity of directly-acting genotoxic agents. At the same time,

carcinogenic

> effects of Ni, directly or in association with organic compounds, have been

> described in the literature, and recently, higher concentrations of Fe and Ni

have

> been found in the malignant human prostate. Inhaled particulate forms of

> hexavalent Cr cause lung cancer, and at the cellular level, Cr exposure may

lead t

> o cell cycle arrest, apoptosis, or neoplastic transformation.

>

> Occupational exposure to Cd is associated with lung cancer in humans, and

> high Cd concentrations have been found in proliferative prostate lesions.

> Interestingly, Zn, as an essential element, was shown to mediate and increase

> tumor growth, and Zn depletion was shown to suppress tumor growth in mice and

> rats. Macromolecular compounds (dextrans) substituted with Hg-containing side

> chains were reported to promote fibrosarcoma growth in mice.

>

> The etiology of the majority of human breast cancers is still controversial.

> However, hormonal influences and environmental toxic compounds inducing

> oxidative stress and lipid peroxidation have been suggested to play a role in

> breast carcinogenesis. Our data describe for the first time a major

accumulation

> of Fe and other transition metals like Ni, Cr, Cd, Zn, Hg, and Pb in the

> breast cancer tissue with implications in the pathogenesis of breast cancer.

>

> Conclusions

> These data suggest that unphysiological gradual accumulation of transition

> metals in the breast tissue may be closely related to the malignant growth

> process. Evaluation of metal exposure through blood, hair, or urine

provocation

> tests, and subsequent chelation treatment may be needed to prevent and treat

> metal-related breast cancer and other malignancies.

>

> Authors

> -Blaurock-Busch Eleonore, PhD, Research Department, Laboratory for Micro

> Trace Minerals, Hersbruck, Germany

> -Eisenmann-Klein Marita, MD, Caritas Hospital St. f, Regensburg, Germany

> -Ionescu Prof. G., PhD, Research Department of Spezialklinik

> Neukirchen, Neukirchen, Germany

> -L?ch Anette, PhD, Research Department of Spezialklinik Neukirchen,

> Neukirchen, Germany

> -Novotny Jan, MD, Institute of Pathophysiology and Oncology,

> University, Prague, Czech Republic

> -Stejskal Assoc. Prof. Vera, PhD, Department of Clinical Chemistry, Danderyd

> Hospital and Karolinska Institute, Stockholm, Sweden

>

**************

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January 13, 2008