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Background: Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases., Methods: We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population., Results: Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population., Conclusions: These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.

Background: In previous work in young women aged 15-30 years we measured breast water and fat using MR and obtained blood for hormone assays on the same day in the follicular phase of the menstrual cycle. Only serum growth hormone levels and sex hormone binding globulin (SHBG) were significantly associated with percent breast water after adjustment for covariates. The sex hormones estradiol, progesterone and testosterone were not associated with percent water in the breast in the follicular phase of the menstrual cycle. In the present study we have examined the association of percent breast water with serum levels of sex hormones in both follicular and luteal phase of the menstrual cycle., Methods: In 315 healthy white Caucasian young women aged 15-30 with regular menstrual cycles who had not used oral contraceptives or other hormones in the previous 6 months, we used MR to determine percent breast water, and obtained blood samples for hormone assays within 10 days of the onset of the most recent menstrual cycle (follicular phase) of the cycle on the same day as the MR scan, and a second blood sample on days 19-24 of the cycle. Serum progesterone levels of > = 5 mmol/L in days 19-24 were used to define the 225 subjects with ovulatory menstrual cycles, whose data are the subject of the analyses shown here., Results: SHBG was positively associated with percent water in both follicular and luteal phases of the menstrual cycle. Total and free estradiol and total and free testosterone were not associated with percent water in the follicular phase, but in young women with ovulatory cycles, were all negatively associated with percent water in the luteal phase., Conclusions: Our results from young women aged 15-30 years add to the evidence that the extent of fibroglandular tissue in the breast that is reflected in both mammographic density and breast water is associated positively with higher serum levels of SHBG, but not with higher levels of sex hormones., Competing Interests: The authors have declared that no competing interests exist.

Background: There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk., Methods: We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided., Results: High-density lipoprotein-cholesterol (HDL-C) (P = .05) and apoA1 (P = .02) levels were positively associated with breast cancer risk (75(th) vs 25(th) percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P = .03) and apoB (P = .01) levels were negatively associated (75(th) vs 25(th) percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk., Conclusions: These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Evidence from animal models shows that tissue stiffness increases the invasion and progression of cancers, including mammary cancer. We here use measurements of the volume and the projected area of the compressed breast during mammography to derive estimates of breast tissue stiffness and examine the relationship of stiffness to risk of breast cancer., Methods: Mammograms were used to measure the volume and projected areas of total and radiologically dense breast tissue in the unaffected breasts of 362 women with newly diagnosed breast cancer (cases) and 656 women of the same age who did not have breast cancer (controls). Measures of breast tissue volume and the projected area of the compressed breast during mammography were used to calculate the deformation of the breast during compression and, with the recorded compression force, to estimate the stiffness of breast tissue. Stiffness was compared in cases and controls, and associations with breast cancer risk examined after adjustment for other risk factors., Results: After adjustment for percent mammographic density by area measurements, and other risk factors, our estimate of breast tissue stiffness was significantly associated with breast cancer (odds ratio = 1.21, 95% confidence interval = 1.03, 1.43, p = 0.02) and improved breast cancer risk prediction in models with percent mammographic density, by both area and volume measurements., Conclusion: An estimate of breast tissue stiffness was associated with breast cancer risk and improved risk prediction based on mammographic measures and other risk factors. Stiffness may provide an additional mechanism by which breast tissue composition is associated with risk of breast cancer and merits examination using more direct methods of measurement.

Background: Some reports suggest that there is a slightly higher frequency of breast cancer in the left breast compared with the right in middle-aged women. The reasons for this association are unknown. The water and fat content of both breasts was compared using magnetic resonance (MR). Breast water by MR reflects fibro-glandular tissue and is strongly positively correlated with percent mammographic density, a strong risk factor for breast cancer., Methods: Magnetic resonance was used to measure fat and water content of the breast in 400 young women aged 15-30 years and a random sample of 100 of their mothers. All MR examinations were carried out using a 1.5T MR system, and 45 contiguous slices were obtained in the sagittal plane. One reader identified the breast tissue in the image, and subsequently, fat and water content was calculated using a three-point Dixon technique. Left- and right-sided images were read independently in random order., Results: In young women, mean percent water was on average 0.84 % higher in the right compared with the left breast (p < 0.001) and total breast water was on average 6.42 cm(3) greater on the right side (p < 0.001). In mothers, there were no significant differences in any breast measure between right and left sides., Conclusion: The small differences in breast tissue composition in young women are unlikely to be associated with large differences in breast cancer risk between sides. The reported excess of left-sided breast cancer in older women is unlikely to be explained by differences in breast tissue composition.

Purpose: To investigate the use of the whole-breast sound speed measurement as a marker of breast density (BD), a known risk factor for breast cancer., Methods: As part of an ongoing study of breast cancer detection, 249 patients were scanned with a clinical prototype that operates on the principles of ultrasound tomography. Typically, 40-100 sound speed tomograms were reconstructed from the scan data, corresponding to the entire volume of the breast of each patient. The data were used to estimate the volume averaged sound speed (VASS) of the breast for each patient. The corresponding mammograms were used to calculate mammographic percent density (MPD) using CUMULUS software. Film mammograms were available for 164 patients while 85 digital mammograms were available for the remaining patients. Standard statistical techniques were used to determine associations of breast sound speed with a variety of mammographic measures such as percent density, area of dense tissue, and area of nondense tissue. Furthermore, associations of breast sound speed with continuous variables such as age and weight and dichotomous variables such as parity and menopausal status were also assessed., Results: VASS was found to be significantly associated with MPD. The Spearman correlation coefficient (r(s)) between VASS and MPD was found to be 0.77 and 0.71 for film and digital mammography, respectively. VASS was positively correlated with dense areas by mammography, both digital (r(s) = 0.46) and film (r(s) = 0.56). VASS was negatively associated with nondense area by mammography, both digital (r(s) = -0.58) and film (r(s) = -0.63). BD by all methods was less in postmenopausal than in premenopausal women. The MPD was lower in the postmenopausal group (by 6.6%, p < 0.08, for the digital group and 7.73%, p < 0.007, for the film group). The VASS was also lower in the postmenopausal group (by 15 m∕s, p < 0.001 for the digital group and 8 m∕s, p < 0.08, for the film group). The association of MPD with age was characterized with r(s) = -0.06 (p < 0.6) for digital mammography and r(s) = -0.53 (p < 0.002) for film mammography. For weight, the MPD associations were characterized by r(s) = -0.53 (p < 0.0001) for digital mammography and -0.38 (p < 0.0001) for film mammography. The association of VASS with age was r(s) = -0.33 (p < 0.002) for the digital group and -0.17 (p < 0.03) for the film group. For weight, the relationship was characterized with r(s) = -0.45 (p < 0.001) for the digital group and -0.37 (p < 0.0001) for the film group., Conclusions: The association between VASS and MPD is strong for both film and digital mammography, suggesting that VASS is a viable measure of breast density. This result sets the stage for future work that will focus on directly testing the association of VASS with breast cancer risk.

Background: Percent mammographic density (PMD) is a strong risk factor for breast cancer that changes in response to changes in hormone exposure. We have examined the magnitude of the association of hormone exposure with PMD according to subsequent breast cancer risk., Methods: In three case-control studies, with 1,164 patient cases and 1,155 controls nested in cohorts of women screened with mammography, we examined the association of PMD measured in the baseline mammogram with risk of breast cancer in the following 1 to 8 years (mean, 3 years), according to use of oral contraceptives (OCs) in premenopausal women, menopause, and hormone therapy (HT) in postmenopausal women. All statistical comparisons are adjusted for age and other risk factors., Results: In premenopausal women who later developed breast cancer (patient cases), PMD was 5.3% greater in past users of OCs than in nonusers (P = .06). In controls, OC users had 2% less density than nonusers (P = .44; test for interaction P = .06). The difference in PMD between premenopausal and postmenopausal women for patient cases was 8.5% (P < .001) and for controls, 3.9% (P = .01; test for interaction P = .03). In postmenopausal women, PMD was 6% greater in patients who used HT than in never users (P < .001). Controls who used HT had 1.6% greater PMD (P = .26) than never users (test for interaction P = .001). Differences in PMD resulted mainly from differences in the dense area of the mammogram., Conclusion: Differences in PMD associated with differences in hormone exposure were greater in women who later developed breast cancer than in controls in each of the hormone exposures examined.

Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.

Percent mammographic density (PMD) is a strong independent risk factor for breast cancer. The effects of age, parity and menopause on PMD are consistent with it being a marker of susceptibility to breast cancer. In this review, we describe the association of PMD with breast cancer, the biological plausibility of this association, and discuss the extent to which PMD meets the criteria for a surrogate marker for the effects of exogenous hormones on risk of breast cancer. Combined hormone therapy is associated with a small increase in both PMD and the risk of breast cancer. However there is evidence that the associations of blood estradiol levels and HRT with breast cancer risk are independent of the association of PMD with risk, suggesting that different biological pathways may be involved. Tamoxifen, an anti-estrogenic drug, reduces both the risk of breast cancer and PMD, but the potential mediation of the effects of anti-estrogens on breast cancer risk by their effects on PMD has not yet been examined. Given the evidence that estradiol and PMD are independently associated with breast cancer risk, it seems unlikely that an effect of these agents on PMD mediates their effects on risk. We thus find that the available evidence is insufficient to conclude that PMD can be used as a surrogate marker for the effect of exogenous hormones on breast cancer. Further research to examine the potential role of PMD as a mediator of the effects of other risk factors is required.

Background: Mammographic density is a heritable quantitative trait and is a strong risk factor for breast cancer in middle-aged and older women. However, little is known about the development of mammographic density in early life. We used MRI to measure the water content of the breast, which provides a measurement of the fibro-glandular content of breast tissue with similar accuracy to mammography, but without the attendant exposure to radiation., Methods: Between December, 2003, and December, 2007, we recruited 400 young women, aged 15-30 years, and their mothers. We used MRI scans to measure daughters' breast water and fat, and on the same day obtained blood for hormone assays in the follicular phase of the menstrual cycle for each young woman. Mothers underwent mammography (n=356), and a random sample (n=100) also consented to have a breast MRI scan., Findings: In mothers, per cent water-as measured by MRI-was strongly correlated with per cent mammographic density (r=0.85). Per cent water in daughters (median 44.8%) was significantly higher than in mothers (median 27.8%; p<0.0001), and was independently inversely associated with both their age (p=0.04) and weight (p<0.0001), and positively associated with their height (p<0.0001) and their mothers' per cent mammographic density (p<0.0001). Serum growth hormone concentrations, adjusted for covariates, were positively associated with per cent breast water (p=0.001) in a subgroup of young women (n=280) who had not used oral contraceptives within 6 months., Interpretation: Per cent breast water was greatest during the ages when women are most susceptible to breast carcinogens, and was associated with weight, height, and mother's breast-tissue characteristics, and with serum concentrations of growth hormone: a breast mitogen that also mediates postnatal somatic growth. Mammographic density in middle age might partly be the result of genetic factors that affect growth and development in early life., Funding: Canadian Breast Cancer Research Alliance.

Mammographic density refers to radiologically dense breast tissue, and reflects variations in the tissue composition of the breast. It is positively associated with collagen and epithelial and non-epithelial cells, and negatively associated with fat. There is extensive evidence that mammographic density is a risk factor for breast cancer, independent of other risk factors, and is associated with large relative and attributable risks for the disease. The epidemiology of mammographic density, notably the inverse association with age, is consistent with it being a marker of susceptibility to breast cancer. Cumulative exposure to mammographic density may be an important determinant of the age-specific incidence of breast cancer in the population. All risk factors for breast cancer must ultimately exert their influence by an effect on the breast, and these findings suggest that, for at least some risk factors, this influence includes an effect on the number of cells and the quantity of collagen in the breast, which is reflected in differences in mammographic density. Many of the genetic and environmental factors that influence the risk of breast cancer affect the proliferative activity and quantity of stromal and epithelial tissue in the breast, and these effects are reflected in differences in mammographic density among women of the same age. Some of these influences include endogenous and exogenous hormones, and the menopause. A better understanding of the factors that influence the response of breast tissue to these hormonal exposures may lead to an improved understanding of the aetiology of mammographic density and of breast cancer.

Background: Some types of hormone therapy increase both risk of breast cancer and mammographic density, a risk factor for the disease, suggesting that mammographic density may be a surrogate marker for the effects of hormones on risk of breast cancer. This research was undertaken to determine whether the effect of hormone therapy on breast cancer risk is mediated by its effect on mammographic density., Methods: Individually matched cases and controls from three nested case-control studies in breast screening populations were studied. Cases had developed invasive breast cancer at least 12 months after the initial screen. Information was collected on hormone use and other risk factors at the time of the baseline mammogram, and percent density was measured by a computer-assisted method., Results: There were 1,748 postmenopausal women, of whom 426 (24.4%) were using hormones at the time of their initial screening mammogram. Current use of hormone therapy was associated with an increased risk of breast cancer (odds ratio, 1.26; 95% confidence interval, 1.0-1.6) that was little changed by adjustment for percent density in the baseline mammogram (odds ratio, 1.19; 95% confidence interval, 0.9-1.5). Percent density in the baseline mammogram was among cases greater in current users of hormones that in never-users (difference = 5.0%, P < 0.001), but the difference was smaller and nonsignificant in controls (difference = 1.6%, P = 0.3)., Conclusion: Although the effects of hormone therapy on mammographic density were greater in cases than controls, we did not find evidence that these effects were causally related to risk of breast cancer.

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., (Copyright 2002 Cancer Research UK)

Menopause has an important influence on risk of breast cancer. We have examined longitudinally the effect of menopause on mammographic densities, a strong risk factor for the disease, in women in the Canadian National Breast Screening Study. Baseline mammograms from women in the National Breast Screening Study, who were premenopausal at entry and had undergone menopause after entry, were compared with the mammogram that most closely followed menopause, using a computer-assisted method of measurement. The changes seen in the mammograms of these subjects were compared with those in an age-matched group of women who were also premenopausal at entry, had been followed for the same length of time, and had not experienced menopause. The results of this longitudinal study show that menopause has effects on characteristics of the mammogram that, over the same period of time, are greater than the effects of age. These effects are a reduction in the area of radiologically dense tissue, an increase in the area of nondense tissue, and a decrease in the percentage of density. However, these changes do not fully account for the effects of age on mammographic densities seen in cross-sectional data. Menopause is associated with distinct changes in the mammogram that account for some, but not all, of the observed association of increasing age with decreasing percentage of mammographic density. The observed changes in the morphology of the breast may explain some of the effect that menopause has on breast cancer risk.