The relation of leptin and adiponectin with breast density among premenopausal women.

The adipocytokine leptin may increase breast cancer risk, while adiponectin may be protective. We examined the association of the two circulating markers with mammographic density, a strong predictor of breast cancer risk. For 183 premenopausal participants of a nutritional trial, mammograms performed at baseline, year 1 and year 2 were assessed for density using a computer-assisted method. Serum samples obtained at the same time were analyzed for leptin and adiponectin by enzyme-linked immunosorbent assay. We applied mixed models to incorporate the repeated measurements while adjusting for confounders including body mass index (BMI). At baseline, the mean age of the participants was 42.6+/-2.9 years; 40% were of Asian ancestry. Leptin was lower and adiponectin higher in normal weight than overweight women. Neither marker was related to absolute breast density. The significant inverse association of leptin with percent density disappeared when BMI was added to the model. After stratification by weight, percent density decreased with higher leptin levels in normal weight women, whereas it increased among overweight participants. After adjustment for BMI, the positive association between percent density and adiponectin was greatly reduced and no longer significant. These results do not support a strong association of leptin or adiponectin with breast cancer risk as assessed by mammographic density. In contrast, the findings suggest the possibility that the inverse association of BMI with breast cancer risk in premenopausal women is mediated by adipocytokines.

Mammographic density and matrix metalloproteinases in breast tissue.

Mammographic density is a strong risk factor for breast cancer, yet the underlying histopathologic correlates are not clear. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play important roles in multiple stages of tumorigenesis. This study examined the association between mammographic density and expression of MMPs 1, 3, 9, and 12 and TIMP3 in benign and malignant breast tissue of 277 women with mainly Caucasian and Japanese ancestry. Tissue microarrays with up to 4 benign and 4 malignant cores per woman were stained immunohistochemically and evaluated. Digitized prediagnostic mammograms were assessed for densities using a computer-assisted method. General linear models adjusted for known confounders were applied to estimate mean densities by staining category. Strong expression of all MMPs was about twice as frequent in malignant as in benign tissue, while TIMP3 expression in stromal tissue was higher in benign than malignant cores. For MMP3 and 9, less than 10% of cores stained positive; thus, they were not further analyzed. None of the markers showed a statistically significant association with breast density in the entire study population and ethnic-specific results were conflicting and difficult to explain. Although not statistically significant, mean density was consistently lower with more extensive TIMP3 expression in stromal and epithelial tissue. These findings indicate that the higher breast cancer risk in women with dense breasts may be influenced by lower TIMP3 expression. However, future investigations into activities and ratios of additional proteases and their inhibitors as well as other pathways, such as inflammation, are needed.

Mammographic density and epithelial histopathologic markers.

BACKGROUND: We explored the association of mammographic density, a breast cancer risk factor, with hormonal and proliferation markers in benign tissue from tumor blocks of pre-and postmenopausal breast cancer cases. METHODS: Breast cancer cases were recruited from a case-control study on breast density. Mammographic density was assessed on digitized prediagnostic mammograms using a computer-assisted method. For 279 participants of the original study, we obtained tumor blocks and prepared tissue microarrays (TMA), but benign tissue cores were only available for 159 women. The TMAs were immunostained for estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor (PR), HER2/neu, Ki-67, and Proliferating Cell Nuclear Antigen (PCNA). We applied general linear models to compute breast density according to marker expression. RESULTS: A substantial proportion of the samples were in the low or no staining categories. None of the results was statistically significant, but women with PR and ERbeta staining had 3.4% and 2.4% higher percent density. The respective values for Caucasians were 5.7% and 11.6% but less in Japanese women (3.5% and -1.1%). Percent density was 3.4% higher in women with any Ki-67 staining and 2.2% in those with positive PCNA staining. CONCLUSION: This study detected little evidence for an association between mammographic density and expression of steroid receptors and proliferation markers in breast tissue, but it illustrated the problems of locating tumor blocks and benign breast tissue samples for epidemiologic research. Given the suggestive findings, future studies examining estrogen effects in tissue, cell proliferation, and density in the breast may be informative.

Inflammatory markers in a 2-year soy intervention among premenopausal women.

BACKGROUND: Epidemiologic evidence supports a role of soy foods in breast cancer etiology. Because chronic inflammation appears to be a critical component in carcinogenesis, we examined the potential anti-inflammatory effects of soy foods. METHODS: The original 2-year dietary intervention randomized 220 premenopausal women of whom 183 women (90 in the intervention group and 93 in the control group) were included in the current investigation; 40% were of Asian ancestry. The intervention group consumed two daily soy servings containing 50 mg of isoflavones (aglycone equivalents), whereas the controls maintained their regular diet. Five serum samples obtained at month 0, 3, 6, 12, and 24 were analyzed for interleukin (IL)-6, C-reactive protein (CRP), leptin, and adiponectin by ELISA. For statistical analysis, mixed models were applied to incorporate the repeated measurements. RESULTS: The levels of all analytes were lower in Asian than Caucasian women. Overweight women had significantly higher levels of CRP, IL-6, and leptin and lower levels of adiponectin than normal weight women. We did not observe a significant effect of soy foods on the four markers, but leptin increased in the control and not in the intervention group (p = 0.20 for group-time effect); this difference was significant for Asian (p = 0.01) and obese women (p = 0.005). CONCLUSION: During this 2-year intervention, soy foods did not modify serum levels of CRP, IL-6, leptin, and adiponectin in premenopausal women although leptin levels remained stable among women in the intervention group who were obese or of Asian ancestry. Further studies with diverse markers of inflammation are necessary to clarify the specific effect of soy on immune responses.