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> Influence of Localized DDT Exposure on Breast Cancer (Research Summary)

[Read the Entire Study]
Initial Award Abstract (2000)

The increase in prevalence of breast cancer over the past 50 years has been speculated to be related to the production and use of many chemicals and pesticides, such as DDT, that have now been shown to have hormonal activities. That is, DDT and other chemicals can mimic or interfere with natural hormonal responses in humans and animals. Therefore, the exposure to these unnatural hormones may disrupt normal responses resulting in accelerated breast cancer development. Some studies in women have suggested that higher levels of the pesticide DDT stored in breast fat increased breast cancer risk, while other studies show no increase in risk, indicating that more evidence is needed to evaluate the role of DDT in breast cancer.

DDT has been banned in the US for about 20 years; however, this pesticide is persistent and remains in the environment and stored in the fat of humans and animals. In addition, DDT remains in use in third world countries; therefore, it continues to invade our environment despite the ban in this country. Every person will carry some level of DDT within their body for their lifetime. In the body and the environment, DDT is broken down into related compounds that have been shown to either act like estrogens or anti-androgen (inhibit the actions of the male sex hormones, androgens). The ability of the DDT compounds to mimic the female sex hormones as well an inhibit the action of the male sex hormones has had devastating consequences on sexual development of wildlife exposed to DDT by environmental contamination. It is reasonable to speculate that the hormonal actions of DDT may be linked to breast cancer, since growth of the cancer-prone cells in the breast is stimulated by estrogens and inhibited by androgens.

Because DDT is not eliminated from our bodies after exposure, remains stored in the fat surrounding the breast tissue where cancer originates, and can act like hormonal agents, DDT has tremendous potential to influence breast cancer. Therefore, we will investigate how localized exposure of these chemicals influence hormonally regulated responses such as growth and tumor development in the mammary glands of mice. We will use a line of mice that develops mammary cancer that frequently progresses to metastatic cancer in the lungs. The cancer in the mice is induced by the most common gene found to be increased in human breast cancer (the oncogene, neu, or HER2). We will locally treat the mammary gland with DDT and assess the effects of DDT on tumor outcomes, such as incidence, age of onset, and progression of the disease to invade the lungs. From these data we will be able to demonstrate that the individual DDT compounds can act like an estrogen or an anti-androgen to influence breast tissue to develop cancer. By determining whether DDT can directly influence growth and tumor development in the breast by mimicking the natural hormones, we can help assess risk in women and devise means to counteract the actions of this chemical prior to tumor onset.

Final Report (2003)

DDT can mimic or interfere with natural hormonal responses in humans and animals; therefore, exposure to these manmade hormone imitators may disrupt normal responses resulting in earlier breast cancer development. In the body and the environment, DDT is broken down into related compounds that have been shown to either act like an estrogen or antiandrogen (inhibits the actions of the male sex hormones). Because DDT is not eliminated from our bodies after exposure, but remains stored in the fat surrounding the breast tissue, and it acts like other hormones, DDT has tremendous potential to influence breast cancer.

In this study, our goals were to determine if the DDT chemicals stored in the breast can influence breast cancer development and if its effects are related to the hormonal activities of this environmental contaminant. The concern about exposure to DDT and breast cancer risk has generally been assigned to the weak estrogen-like activities of some DDT compounds. However, the most abundant DDT chemical has not been considered despite its strong anti-androgen activity. We were concerned that this prevalent and potent DDT compound needed to be tested for its potential to influence the development of breast tumors. In this study, two individual DDT chemicals with the different hormone activities (estrogenic and anti-androgenic) are examined for their influence on cancer development using a mouse model that develops mammary cancer caused by the most common cancer causing gene in human breast cancer (the oncogene, neu, erbB2, or HER2), no treatments include two DDT compounds, one with estrogen-like activity (o,p DDE) and the other with anti-androgen activity (pp DDE). These were compared to groups treated with a known estrogen (one naturally produced in women) and anti-androgen (one used to treat prostate cancer).

Treatments are designed to only affect the mammary gland, and not the entire body, to determine if DDT found in breast fat influences cancer formation. The anti-androgenic DDT chemical, pp DDE, was the most active at causing the mammary tumors to begin at younger ages. The average age that mammary tumors were first detected in the p,p DDE exposed females was almost a month and a half earlier than the control group (7.6 mo, n=58, vs, 9.0 mo, n=53). However, only a weak effect was observed for the o,p DDE treated females, with the latency more than 2 weeks earlier than the control group (n=50). These data indicate that the accumulation of DDE in adipose tissue proximal to the cancer-prone epithelial cells can promote tumor development.

The earlier onset of tumors suggests that p,p DDE could substantially reduce the number of cancer-free years in a woman’s life. However, when p,p and o,p DDE were given in comb ination.(2:1 ratio), the earlier onset of mammary cancer was lost. These data suggest that the two DDE isomers do not act similarly to influence tumor development, and may even act in opposition, suggesting that the ratio of DDT metabolites may be important in assessing DDT’s influence on breast cancer risk. The results with one potential ratio of pp DDE to o,p DDE that may occur in nature suggests that the ratio these two compounds of may be important to how DDT influences cancer risk. These results may explain one reason for the conflicting data from studies in women reporting both that DDT increases and does not influence breast cancer risk. Since p,p DDE is the most prevalent metabolite of DDT, these data suggest that ratios with higher proportions of p,p. DDE may be more likely to accelerate tumor development. 1`si conclusion, our study demonstrates that local stores of DDT metabolites can influence the onset of mammary cancer induced by the most common oncogene in human breast cancer (erbB2 or HER2/neu), with the anti-androgenic isomer, p,p DDE, having the most consequential impact.

Symposium Abstract (2005)

Since the risk of breast cancer in women has risen in the past few decades, many have speculated this may be due to increased exposures to chemicals, especially as contaminants in our environment. One chemical of interest is the pesticide DDT. DDT was heavily used in the U.S. in 1950’s until its ban in the 1970’s. DDT is composed of several compounds that can mimic hormones, like estrogens. These hormone-like activities have been associated with detrimental reproductive effects on wildlife in DDT polluted regions. The estrogenic activity of DDT compounds also raised concern for breast cancer risk since DDT is stored in fat, which is a primary component in the breast. In addition, DDT is very stable. Thus, DDT is stored, and accumulates with additional exposures, in the breast fat, right next to the cells that are stimulated by hormones and prone to develop into cancer. Studies in women have shown mixed reports as to whether DDT levels influence breast cancer risk. Since our bodies still contain DDT from exposures before the U.S. ban and it is still used in other countries, we investigated whether DDT stored in breast fat could influence breast cancer development. To do this, we tested 2 DDT compounds (o,p DDE and p,p DDE), alone and combined, on mammary cancer development in a mouse model that mimics HER2+ breast cancer. The o,p DDE, has estrogen-like activity. The p,p DDE compound is the most prevalent form found in the environment and stored in fat. It has antiandrogen-like activity; that is, it can inhibit the actions of androgens, such as testosterone.

The female mice were treated so that the DDT compounds would be stored primarily in the mammary glands. We examined how many of the females developed mammary cancer and when the tumors were first detected. Although both DDT compounds caused the mammary tumors to occur at younger ages, the anti-androgenic p,p DDE had the strongest effect. The average age that mammary tumors were first detected in the p,p DDE exposed females was almost a month and a half earlier than the control group. However, the tumors only appeared 2 weeks earlier for the o,p DDE treated females. These data indicate that the accumulation of DDE in mammary tissue can adversely influence tumor development. Since a month in a mouse’s life is comparable to many years in a woman, the earlier onset of tumors suggests that p,p DDE could substantially reduce the number of cancer-free years in a woman’s life. However, when p,p and o,p DDE were given in combination (2:1 ratio), the mammary tumors did not develop earlier. These data suggest that the ratio of DDT metabolites, which will vary with different individuals, may be important in assessing DDT’s influence on breast cancer risk. Therefore, the individual variation in ratios may account for the mixed results in studies investigating DDT and breast cancer risk.
Cedars-Sinai Medical Center Open Window
Investigator(s): Vicki Davis , Ph.D. –
Award Type: Innovative Awards > IDEAS II
Award Cycle: 2000 (Cycle VI) Grant #: 6JB-0004 Award Amount: $305,989

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