Cadmium Exposure and Risk of Breast Cancer by Histological and Tumor Receptor Subtype in White Caucasian Women: A Hospital-Based Case-Control Study.

As the majority of experimental studies suggest cadmium being metalloestrogen, we examined cadmium/breast cancer (BC) association by histological and tumor receptor subtype in 509 invasive BC patients and 1170 controls. Urinary cadmium was determined by atomic absorption spectrometry, and categorized using tertiles of its distribution in the controls: <0.18, 0.18-0.33, >0.33 kg × 10-9/kg × 10-3 creatinine. Relative to the lowest category of urinary cadmium adjusted odds ratio (OR) of ductal BC was 1.18 (95% confidence interval (CI): 0.89-1.58) in the intermediate and 1.53 (95% CI: 1.15-2.04) in the highest category. There was a significant association for hormone receptor-positive ductal BC: ORs per category increase were 1.34 (95% CI: 1.14-1.59) for estrogen receptor-positive (ER+), 1.33 (95% CI: 1.09-1.61) for progesterone receptor-positive (PR+) and 1.35 (95% CI: 1.11-1.65) for ER+/PR+ BC. We found a significant association between cadmium and human epidermal growth factor receptor 2-negative (HER2-) ductal BC. The strongest association with cadmium was for ER+/PR+/HER2- ductal BC. The associations between cadmium and lobular BC with hormone receptor-positive and HER2- were positive but insignificant. There was no evidence that the associations with cadmium differed for cancers with different tumor histology (p-heterogeneity > 0.05). This study provides evidence that urinary cadmium is associated with the risk of hormone receptor-positive and HER2- breast cancer independent of tumor histology.

Urinary estrogen metabolites and breast cancer: a combined analysis of individual level data.

BACKGROUND: Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and their ratio (2:16α-OHE1) in relation to breast cancer risk. METHODS: Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using enzyme linked immunosorbent assays. Study-specific and combined multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated based on tertiles of estrogen metabolites. Multinomial logistic regression models were fit according to hormone receptor status.
 RESULTS: Higher premenopausal 2:16α-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16α-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvsI=0.93; 95% CI: 0.65-1.33); however, the association between 2-OHE1 and risk varied by body mass index (p-interaction=0.003). CONCLUSIONS: Premenopausal urinary 2:16α-OHE1 may play a role in breast carcinogenesis; however, larger studies are needed. Our findings do not support reduced breast cancer risk with higher postmenopausal 2:16α-OHE1 overall, although obesity may modify associations with 2-OHE1.

Potential of fluorescent metalloproteinase substrates for cancer detection.

OBJECTIVES: MMP-2, MMP-9, their complexes and ADAM12 are detected in the urine of breast cancer patients and predict disease status. We assessed the use of FRET-based substrates in an assay to distinguish breast cancer patients from controls. DESIGN AND METHODS: Substrates with varying specificities for MMP-9 and MMP-2 and several ADAMs were screened. Flsub21 and Flsub13, substrates for ADAM12 and ADAM8 respectively, were studied. RESULTS: Flsub21 and Flsub13 cleavage activities were detected in the urine of patients with invasive and metastatic breast cancers at significantly higher frequencies compared to controls. Our model predicted probabilities of 90% when both Flsub21 and Flsub13 were positive, 65% when Flsub21 alone was positive, 55% when Flsub13 alone was positive and 20% when both substrates were negative. CONCLUSIONS: These data suggest the potential utility of FRET substrates to non-invasively identify invasive and/or metastatic breast cancer.

Comparison of estrogens and estrogen metabolites in human breast tissue and urine.

BACKGROUND: An important aspect of the link between estrogen and breast cancer is whether urinary estrogen levels are representative of the intra-tissue levels of bioavailable estrogens. METHODS: This study compares 15 estrogen and estrogen metabolite levels in breast tissue and urine of 9 women with primary breast cancer using a quantitative liquid chromatography-mass spectrometry method. RESULTS: The average levels of estrogens (estrone, 17 beta-estradiol) were significantly higher in breast tissue than in urine. Both the 2 and the 16-hydroxylation pathways were less represented in breast tissue than urine; no components of the 4-hydroxypathway were detected in breast tissue, while 4-hydroxyestrone was measured in urine. However, the 2/16 ratio was similar in urine and breast tissue. Women carrying the variant CYP1B1 genotype (Leu/Val and Val/Val) showed significantly lower overall estrogen metabolite, estrogen, and 16-hydroxylation pathway levels in breast tissue in comparison to women carrying the wild type genotype. No effect of the CYP1B1 polymorphism was observed in urinary metabolites. CONCLUSIONS: The urinary 2/16 ratio seems a good approximation of the ratio observed in breast tissue. Metabolic genes may have an important role in the estrogen metabolism locally in tissues where the gene is expressed, a role that is not readily observable when urinary measurements are performed.

Biomonitoring of urinary tamoxifen and its metabolites from breast cancer patients using nonaqueous capillary electrophoresis with electrospray mass spectrometry.

Tamoxifen is an antiestrogen drug used to treat breast cancer. We have extracted tamoxifen and several of its metabolites from urine of patients with both metastatic (stage IV) and locally confined (stages I, II, and III) breast cancer. Analysis of these metabolites was performed by nonaqueous capillary electrophoresis with electrospray-mass spectrometry. Peak heights from extracted ion current electropherograms of the metabolites were used to establish a metabolic profile for each patient. We demonstrate substantial variation among patient profiles, statistically significant differences in the amount of urinary tamoxifen N-oxide found in stages I, II, and III compared to stage IV breast cancer patients, and statistically significant differences in the amount of 3,4-dihydroxytamoxifen found in progressors compared to nonprogressors with metastatic (stage IV) cancer.