The association of breast mitogens with mammographic densities

Abstract

Radiologically dense breast tissue (mammographic density) is strongly associated with risk of breast cancer, but the biological basis for this association is unknown. In this study we have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer.

Pre-diagnosis physical activity and mammographic density in breast cancer survivors

“…Physical activity may influence mammographic density by favorably changing certain hormones that may be associated with mammographic density, such as sex steroid hormones. Many published studies have shown an effect of exogenous estrogens on increasing mammographic density (19), however, the only published study that examined the association between mammographic density and endogenous estrogens observed no association between total estradiol and percent density in both pre-and postmenopausal women, and an inverse association between free estradiol and percent dense tissue in postmenopausal women (20). The hypothesized mechanism of physical activity influencing mammographic density via sex hormone changes applies especially to obese postmenopausal women, who have higher levels of sex hormone concentrations than leaner postmenopausal women, due to the formation of estrogens in fatty tissue (10,21,22).…”

Insulin-like growth factor-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women

“…Some studies have examined the GH-IGF signaling pathway in association with mammographic density, for both premenopausal and postmenopausal women, but the results are indifferent [43,44,34]. For postmenopausal women, however, the growth factor levels, estrogen levels and mammographic densities are lower than that for premenopausal women.…”

“…For postmenopausal women, however, the growth factor levels, estrogen levels and mammographic densities are lower than that for premenopausal women. This may explain in part, why no associations between these growth factors and mammographic density have been observed for postmenopausal women [34,35,43]. Thus, the higher levels of cyclic estrogen and serum level of growth factors may be more likely to capture the aetiologically relevant exposure period, and may explain in part why the associations are more pronounced among premenopausal women [45].…”

Breast composition: Measurement and clinical use

“…48 The second mechanism involves biological interaction among epithelial and stromal cells, collagen and the breast microenvironment. 32,33 It has been shown that mitogenic followed by mutagenic activity are at least in part, responsible for high breast density and breast cancer, where individuals with both high breast density and breast cancer demonstrate similar mitogen 47 and mutagen characteristics. 48 It is well known that mitogens induce cell proliferation, primarily affecting epithelial and stromal cells leading to increased fibroglandular tissue and higher levels of breast density mostly in premenopausal women.…”

“…43,46 Mechanisms linking breast density to breast cancer Two theories have been postulated to explain the mechanisms linking breast density and breast cancer. The first mechanism involves mitogen (a chemical substance that encourages a cell to commence cell division, triggering mitosis), 47 and mutagen effects (a physical or chemical agent that changes the genetic material of an organism and thus increases the frequency of mutations above the natural background level). 48 The second mechanism involves biological interaction among epithelial and stromal cells, collagen and the breast microenvironment.…”