Accumulation of environmental estrogens in adipose tissue of breast cancer patients.

Although the estrogenic properties of numerous chloroorganic pesticides have been widely recognized, population studies do not give clear results indicating the link between the exposure to these compounds and breast cancer development. Because of the weak affinity of these pesticides to estrogen receptors, they probably act by affecting the expression of CYP genes encoding cytochromes P450 engaged in the metabolism of environmental as well as natural estrogens. To examine the possible correlation between environmental estrogen levels in adipose tissue and breast cancer stage, grade, receptor status and onset of the disease, adipose tissue was isolated from 54 breast cancer patients and 23 healthy individuals. Clinical characteristics were obtained from the medical records, while the information concerning exposure to environmental estrogens where obtained from questionnaires. The environmental estrogens were identified and quantified by GC-chromatography. The data was analyzed with the use of Student t-test and Spearman correlation. The levels of most environmental estrogens did not differ between the patients and the controls, except the beta-HCH (beta-hexachlorocyclohexane) level, which was higher in the patients than in the healthy individuals. Significantly higher levels of DDE (1,1-bis(4-chlorophenyl)-2,2-dichloroethene) and DDT (1,1,1-trichloro-2,2-bis(4-chlorophenol)ethane) (P < 0.05) were observed in the patients with late onset of the disease which was probably due to the time of exposure. Moreover, in the patients exposed to environmental estrogens, significantly higher concentrations of DDD (1,1-bis(4-chlorophenyl)-2,2-dichloroethane) were found (P < 0.05). We also evidenced that estrogen-independent cancer was more frequent in the patients exposed to numerous risk factors in which higher levels of HCB (hexachlorobenzene), gamma-HCH (gamma-hexachlorocyclohexane), DDD and DDT in adipose tissue were detected. Breast cancer development is probably related to the accumulation of DDT and its derivatives, but the effect appears only in older patients. We postulate that environmental estrogens acting together with other risk factors might influence the progress and exacerbate the prognosis of breast cancer.

Studies on CYP1A1, CYP1B1 and CYP3A4 gene polymorphisms in breast cancer patients.

BACKGROUND: The role of CYP1A1, CYP1B1 and CYP3A4 polymorphism in pathogenesis of breast cancer has not been fully elucidated. From three CYP1A1 polymorphisms *2A (3801T>C), *2C (2455A>G), and *2B variant, which harbors both polymorphisms, the *2A variant is potentially carcinogenic in African Americans and the Taiwanese, but not in Caucasians, and the CYP1B1*2 (355G>T) and CYP1B1*3 (4326C>G) variants might increase breast cancer risk. Although no association of any CYP3A4 polymorphisms and breast cancer has been documented, the CYP3A4*1B (392A>G) variant, correlates with earlier menarche and endometrial cancer secondary to tamoxifen therapy. OBJECTIVE: The present study was designed to investigate the frequency of CYP1A1, CYP1B1 and CYP3A4 polymorphisms in a sample of breast cancer patients from the Polish population and to correlate the results with the clinical and laboratory findings. MATERIAL AND METHODS: The frequencies of CYP1A1*2A; CYP1A1*2C; CYP1B1*3; CYP3A4*1B CYP3A4*2 polymorphisms were determined in 71 patients aged 36-87, with primary breast cancer and 100 healthy individuals. Genomic DNA was extracted from the tumor and individual gene fragments were PCR-amplified. The polymorphisms were determined by RFLP and were correlated with the patients' TNM stage, grade, estrogen and progesterone receptor status as well as the level of c-erbB-2 protein. RESULTS: CYP1A1 polymorphisms were more frequent in younger patients and in the patients with high level of c-erbB-2 protein. No correlation between these polymorphisms and the cancer stage or grade, as well as the receptor status was demonstrated. CONCLUSIONS: CYP1A1 polymorphisms probably predispose to an earlier onset of breast cancer and might be associated with higher c-erbB-2 protein level, but further studies on a much larger group are required to substantiate our findings.

The effect of indole-3-carbinol on the expression of CYP1A1, CYP1B1 and AhR genes and proliferation of MCF-7 cells.

The influence of an antiestrogen, indole-3-carbinol (I3C) on the expression of CYP1A1, CYP1B1 and AhR genes was investigated in an attempt to establish whether I3C could increase the expression of genes involved in estrone metabolism. Another purpose was to examine the proliferation of an estrogen-dependent breast cancer cell (MCF-7 line) under the influence of I3C and both I3C and DDT. In MCF-7 cells incubated with I3C or I3C and DDT combined, quantitative RT-PCR analysis revealed a significant increase in the level of CYP1A1, AhR, and CYP1B1 transcripts. The proliferation rate of MCF-7 cells was increased by treatment with DDT or estradiol (E2), whereas I3C did not affect the proliferation of MCF-7 cells but greatly reduced the stimulatory effect of DDT, and abolished the effect of E2. The level of p21 transcript, encoding p21 protein involved in the cell cycle, was increased several-fold by I3C comparing to its level in cells incubated with estradiol or DDT. The results suggest that the proliferation of MCF-7 cells is accompanied not only by expression of genes encoding cytochromes involved in estrogen metabolism, but also by changes in the expression of other genes including that encoding p21 protein involved in the cell cycle.