The present prospective study was designed to investigate the associations of caffeinated coffee and black tea consumption with risk of breast cancer overall and by hormone receptor status. The study included 61,433 women in the Swedish Mammography Cohort who were cancer free during the baseline enrollment period of 1987 to 1990. Coffee and tea intake was determined using a food-frequency questionnaire administered both at baseline and in 1997. Swedish cancer registers were accessed to obtain information concerning the incidence and nature of newly diagnosed invasive breast cancers in the study cohort. During an average follow-up period of 17.4 years (through year-end 2007), 2,952 incident cases of invasive breast cancer were found. Coffee consumption was found not to be associated with overall risk of breast cancer (multivariate relative risk (RR) for at least four cups per day compared to less than one cup per day = 1.02; 95% confidence interval (CI) = 0.87 - 1.20). Nor was any association found between coffee consumption and breast cancer subtype defined by estrogen receptor (ER) and progesterone receptor (PR) status. On the other hand, black tea intake was found to be significantly positively associated with risk of breast cancer overall and ER+/PR+ tumors in particular. The multivariate RRs comparing at least two cups of black tea per day with no consumption were 1.22 (95% CI = 1.05 - 1.42) for breast cancer overall and 1.36 (95% CI = 1.09 - 1.69) for ER+/PR+ breast cancer. The authors conclude that the study findings do not support a role of coffee consumption in the development of breast cancer. However, the results suggest that black tea may be positively associated with risk of ER+/PR+ breast cancer.

The current study examined the prevalence of the eight possible combinations of ER/PR/HER2 status in California breast cancer patients in conjunction with five-year survival. Breast cancer generally is categorized according to the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). The California Cancer Registry was used to classify 61,309 women with primary invasive breast cancer according to ER/PR/HER2 status and five-year relative survival was computed for all possible combinations of subtypes. Odds ratios (ORs) were estimated using multivariate logistic regression. Women who were younger than 50 at diagnosis, African American, Hispanic, of low socio-economic status, and/or with stage IV undifferentiated tumors were more likely to have breast cancer with an ER-negative subtype (ER-/PR-/HER2+ or ER-/PR-/HER2- (triple negative)). Asian Pacific Islanders also had increased odds of having the ER-/PR-/HER2+ subtype (OR = 1.41; 95% confidence interval (CI) = 1.26–1.57). Stage III tumors (OR = 1.25; 95% CI = 1.08–1.44) and stage IV tumors (OR = 1.58; 95% CI = 1.27–1.98) were more likely than stage I tumors of being ER-/PR-/HER2+. Stage IV tumors were much less likely to be of the ER-/PR-/HER2- subtype (OR = 0.54; 95% CI = 0.44–0.67). Poorly differentiated and undifferentiated tumors were found to be more than 20 times as likely as well-differentiated tumors to be hormone receptor negative. Survival was found to vary from 96% for hormone receptor-positive/HER2 negative breast cancer (ER+/PR+/HER2-) to 76% for hormone receptor-negative breast cancer (including both ER-/PR-/HER2+ and triple negative). The four subtypes found to have the poorest survival were all ER-. The authors recommend reporting breast cancer as an ER/PR/HER2 subtype and precisely documenting demographic and tumor characteristics.

The present study was designed to examine the association between alcohol consumption and breast cancer in postmenopausal women by breast cancer type. The study group included 184,418 postmenopausal women 50 to 71 years old in the National Institutes of Health-AARP Diet and Health Study (1995–2003). A mailed questionnaire was used at baseline to assess alcohol use, diet, and potential risk factors for cancer. Relative risks and 95% confidence intervals were calculated by using Cox proportional hazards regression. State cancer registries were used to identify breast cancer cases and estrogen receptor and progesterone receptor status. During a mean seven year follow-up period, 5,461 breast cancer cases were identified. Alcohol consumption was found to be significantly positively associated with risk of breast cancer: Even a moderate amount of alcohol (greater than 10 g/day) was shown to significantly increase risk of breast cancer. In a comparison of greater than 35 g per day versus no alcohol intake, the multivariate relative risks were found to be 1.35 (95% confidence interval (CI): 1.17-1.56) for total breast cancer, 1.46 (95% CI: 1.22-1.75) for ductal breast cancer, and 1.52 (95% CI: 0.95-2.44) for lobular tumors. The multivariate relative risk for estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) tumors was 1.46 (95% CI: 1.12-1.91) for greater than 35 g per day versus no alcohol intake. The estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) multivariate relative risk was 1.13 (95% CI: 0.73-1.77) for greater than 20 g versus no alcohol intake. The estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) multivariate relative risk was 1.21 (95% CI: 0.79-1.84) for greater than or equal to 20 g versus no alcohol intake. The authors conclude that moderate consumption of alcohol is associated with breast cancer, especially hormone receptor-positive tumors.

The present study investigated the effects of genistein on CYP19 regulation in HepG2 liver cells. Genistein is considered a selective estrogen receptor modulator since it displays different binding affinity to different estrogen receptor (ER) isoforms. Aromatase or CYP19 is highly expressed in the ovary, which is the primary source of estrogen in pre-menopausal women. After menopause, when the ovaries stop producing the hormone, localized estrogen synthesis in other tissues become more significant physiologically. In the study, genistein was found to induce aromatase activity in HepG2 cells. Several protein kinases were examined and PKCα, P38, and ERK-1/2 were found to be involved. The transcriptional factor CREB was also found to be activated in the gene regulation. The authors comment that the study illustrated an extragonadal pathway by which genistein might increase estrogen synthesis.

The present study was designed to examine the time-varying effects of tumor characteristics on breast cancer survival. While early detection and better treatments have improved survival, the risk of relapse remains long beyond diagnosis. Therefore, identifying prognostic factors for late breast cancer recurrence and metastasis is important. The study included data concerning breast-cancer-free survival for 3,088 breast cancer cases in four U.S. states. The subjects had participated in a randomized dietary intervention trial during 1995–2006. The median follow-up period was nine years; the maximum was 15 years. To allow for deviations from the proportional hazards assumption, a piecewise constant penalized spline approach incorporating time-varying coefficients was used. This method provides direct estimates of hazard ratios across time intervals. During the first 2.5 years after diagnosis, Stage II or III breast cancer at diagnosis was found to be associated with a three-fold higher risk of breast cancer compared to stage I breast cancer. While this hazard ratio decreased to 2.1 after 7.7 years, higher tumor stage persisted as an important risk factor. Similar diminishing effects over time were found for poorly differentiated tumors. Having estrogen receptor-positive (ER+) breast was protective up to four years after diagnosis. However, ER+ tumor status was found to be detrimental after 7.7 years (hazard ratio = 1.5). The authors comment that the results emphasize the importance of modeling that allows for time-dependent effects in long-term breast cancer survivorship studies.

The present study was designed to evaluate the association between dietary and supplemental intakes of carotenoids and vitamins C and E and the risk of breast cancer according to estrogen receptor (ER) and progesterone receptor (PR) status. The study group included 84,805 postmenopausal women in the Women's Health Initiative Observational Study. During an average follow-up period of 7.6 years, there were 2,879 new cases of invasive breast cancer, of which 2,509 had receptor data. Dietary α-carotene (highest versus lowest quintile: RR = 0.83; 95% CI = 0.70- 0.99; P for trend = 0.019), β-carotene (highest versus lowest quintile: RR = 0.78; 95% CI = 0.66-0.94; P = 0.021), and lycopene (highest versus lowest quintile: RR = 0.85; 95% CI = 0.73-1.00; P = 0.064) were each found to be inversely associated with the risk of ER+/PR+ breast cancer, but not with other breast cancer groups as defined by ER and PR status. Total or supplemental β-carotene and dietary intakes of lutein+zeaxanthin and β-cryptoxanthin were not found to be associated with breast cancers defined by ER and PR status. Vitamin E (regardless of source) and dietary vitamin C were found not to be associated with breast cancer. However, both total (dietary plus supplemental) and supplemental vitamin C intake were found to be weakly positively associated with breast cancer. The authors conclude that dietary intake of certain carotenoids might be differentially associated with risk of invasive breast cancers jointly defined by ER and PR status among postmenopausal women.

The current prospective study was designed to examine the associations of several known breast cancer risk factors by estrogen receptor (ER) and progesterone receptor (PR) status in the large prospective Multiethnic Cohort study. The study included 46,079 women with natural menopause or bilateral oophorectomy who provided risk data at baseline by means of a questionnaire. During a follow-up period averaging 8.3 years, 1,339 new cases of breast cancer were diagnosed for which information on ER/PR status was available. There were 902 women with ER+/PR+ breast cancer, 231 with ER-/PR-, 173 with ER+/PR-, and 33 with ER-/PR+. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) for breast cancer incidence by ER/PR status associated with each risk factor were calculated using Cox log-linear proportional hazard models stratified by age at recruitment to the study, year of recruitment, race/ethnicity, and study area, and adjusted for potential confounders. Compared with women having a body mass index (BMI) of less than 25 kg/m2, those with BMIs of at least 30 kg/m2 were found to have an increased risk of ER+/PR+ breast cancer (RR=1.51, 95% CI: 1.24 - 1.85) and a reduced risk of ER-/PR- tumors (RR=0.62, 95% CI 0.40 - 0.96). Late age at first period (15 years versus 12 years old) (RR=0.72, 95% CI: 0.57 - 0.91), early age at first birth ( 20 years vs. nulliparous) (RR=0.69, 95% CI: 0.51 - 0.94), and increasing number of children (p trend <0.001) were found to be significantly associated with reduced risk only among those with ER+/PR+ tumors. Current use of postmenopausal estrogen only (ET) and estrogen-progestin combined therapy (EPT) both were found to be associated with increased risk of ER+/PR+ tumors (RR for ET=1.51, 95% CI: 1.16 - 1.97; RR for EPT=2.33, 95% CI: 1.97 - 2.75) and ER+/PR- (RR for ET=1.94, 95% CI: 1.09 - 3.44; RR for EPT=1.43, 95% CI: 0.97 - 2.12) tumors only. Consumption of alcohol was found to increase breast cancer risk for all ER/PR subtypes; compared to nondrinkers, women who drank at least two drinks per day had RRs varying from 1.5 to 2.6. Similarly, a family history of breast cancer was found to be associated with heightened risk of breast cancer independent of ER/PR status, with the RRs varying from 1.4 to 1.9.

The current prospective study was designed to investigate the associations between plasma concentrations of folate, pyridoxal 5-phosphate (the principal active form of vitamin B-6 (B-6)), and vitamin B-12 and risk of breast cancer. B vitamins such as folate, vitamin B-6, and vitamin B-12 are important for DNA integrity and stability. Hence, deficiency in any of these vitamins is thought to have the potential to promote carcinogenesis. Study participants were drawn from the 28,345-member Women's Health Study cohort. Participants provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. The study current included 848 incident cases of invasive breast cancer identified as of month-end March 2004, as well as 848 matched control subjects. Logistic regression controlling for matching factors and other risk factors for breast cancer was performed to calculate relative risks (RRs) and 95% confidence intervals (CIs). Plasma concentrations of folate, B-6, and vitamin B-12 were found not to be associated with overall breast cancer risk. Women in the highest fifth relative to those in the lowest quintile had multivariate RRs of 1.42 (95% CI: 1.00 - 2.02) for plasma folate (P for trend = 0.21), 0.91 (95% CI: 0.63 - 1.30) for plasma B-6 (P for trend = 0.48), and 1.29 (95% CI: 0.92 - 1.82) for plasma vitamin B-12 (P for trend = 0.18). However, it was found that higher plasma folate concentrations were associated with increased risk of developing premenopausal breast cancer (P for trend = 0.04) and for developing estrogen receptor positive (ER+) or progesterone receptor positive (PR+) tumors (P for trend 0.06). On the other hand, an inverse association was found between plasma B-6 and postmenopausal breast cancer (P for trend = 0.04). The authors conclude that folate, vitamin B-6, and vitamin B-12, may confer little or no reduction in overall risk of developing breast cancer. The observed positive associations of serum folate with risk of developing premenopausal breast cancer and ER+ or PR+ tumors were unexpected and require additional research to elucidate the role of folate in breast cancer development.

The present study was designed to evaluate the potential estrogenic and anti-estrogenic activities of Avlimil, a dietary supplement advertised to increase female sexual response. Avlimil is a mixture of eleven herbs, and some of these herbs (black cohosh, licorice, red raspberry, red clover and kudzu) contain compounds which have been suggested to have estrogenic, anti-estrogenic, or androgenic potential for relieving menopausal symptoms. In the study, Avlimil was investigated to see if it could modulate the growth of estrogen receptor positive (ER+) human breast cancer (MCF-7) cells in vitro and in vivo. A dimethylsulfoxide extract of Avlimil was tested for its estrogenic and anti-estrogenic effects on the growth of MCF-7 cells in vitro. The Avlimil extract at low concentrations (0.1–50 μg/mL media) was found to increase MCF-7 cell proliferation in a dose-dependent manner, whereas Avlimil extract at 100 μg/mL inhibited the growth of MCF-7 cells. Avlimil and some of its components (black cohosh and licorice roots) of Avlimil were fractionated using sequential solvent extraction and the activities of the fractions were monitored with respect to effects on the growth of MCF-7 cells. Depending on dosage, both stimulatory and inhibitory effects on the growth of MCF-7 cells were observed. Next, the effect of dietary Avlimil at dosages approximating human intake was studied using ovariectomized mice implanted with MCF-7 cells. The mice were fed diets containing 500 ppm or 1000 ppm Avlimil for 16 weeks. Dietary Avlimil at 500 ppm was found to stimulate the growth of MCF-7 tumors, but Avlimil at 1000 ppm had no observable effect on MCF-7 tumors. The authors comment that the study observation of increased tumor growth in the absence of uterine weight gain indicate that the observed estrogenic/anti-estrogenic effects of Avlimil may be dosage- and target tissue-specific and that Avlimil may not be safe for women with estrogen-dependent breast cancer.

The current prospective study investigated the associations between physical activity, diet, and obesity and survival after breast cancer diagnosis. Study participants included 1,490 women diagnosed and treated for early-stage breast cancer between 1991 and 2000. The women were enrolled in the study at two years post diagnosis on average. Seven women were lost to follow-up through December 2005. In single-variable analysis, reduced mortality was found to be weakly associated with higher vegetable-fruit consumption, increased physical activity, and a body mass index that indicated neither low weight nor obesity. In a multivariate Cox model, only the combination of consuming five or more daily servings of vegetables/fruits plus accumulating at least 540 metabolic equivalent tasks-minutes per week (equivalent to walking 30 minutes, six days per week) was found to be associated with a significant survival advantage (hazard ratio, 0.56; 95% confidence interval, 0.31-0.98). The approximate 50% reduction in breast cancer metastasis risk associated with these behaviors was found in both obese and nonobese women, although fewer obese women were physically active with a high vegetable/fruit intake. In other words, among those who adhered to this healthy lifestyle, there was no observable effect of obesity on survival. The effect was stronger in women who had hormone receptor-positive (ER+/PR+) cancers.

The current prospective study examined the associations between the risk of invasive breast cancer in postmenopausal women and dietary intakes of four plant lignans (pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol) and estimated exposure to two enterolignans (enterodiol and enterolactone). The study included 58,049 postmenopausal French women who were not taking soy isoflavone supplements. The women completed a self-administered diet history questionnaire. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards regression models. Analyses were stratified by tumor combined estrogen and progesterone receptor (ER/PR) status. During a median follow-up period of 7.7 years, 1,469 cases of breast cancer were diagnosed. Women in the highest quartile of total lignan intake (greater than 1,395 µg per day) were found to have a reduced risk of breast cancer (RR = 0.83, 95% CI = 0.71-0.95, Ptrend = .02) compared to women in the lowest quartiles, as did those in the highest quartile of lariciresinol intake (RR = 0.82, 95% CI = 0.71-0.95, Ptrend = .01). The inverse associations between phytoestrogen intakes and postmenopausal breast cancer risk were restricted to ER+ and PR+ disease (RR for highest versus lowest quartiles of total plant lignan intake = 0.72, 95% CI = 0.58 - 0.88, Ptrend = .01). The authors conclude that high dietary intakes of plant lignans and high exposure to enterolignans are associated with reduced risks of ER+/PR+ postmenopausal breast cancer in a Western population that does not consume a diet rich in soy.

The present prospective study was designed to examine the association between red meat intake and breast cancer by hormone receptor status among premenopausal women. Study participants included 90,659 women ages 26 to 46 years in the Nurses' Health Study II. Red meat intake was determined by a food frequency questionnaire administered in 1991, 1995, and 1999. Respondents were followed up through year-end 2003. Breast cancer cases were self-reported and confirmed by review of pathologic reports. During a follow-up period of 12 years, 1,021 new cases of invasive breast carcinoma were documented. Greater red meat intake was found to be strongly associated with elevated risk of breast cancers that were estrogen and progesterone receptor positive (ER+/PR+; n = 512) but not to cancers that were estrogen and progesterone receptor negative (ER–/PR–; n = 167). Compared to those consuming fewer than four servings of red meat per week, the multivariate relative risks (95% confidence intervals) for ER+/PR+ tumors with increasing servings of red meat intake were (a) 1.42 (1.06-1.90) for five to seven servings per week; (b) 1.20 (0.89-1.63) for seven to 10 1/2 servings per week; and (c) 1.97 (1.35-2.88) for more than 10 1/2 servings per week (test for trend, P = .001). The corresponding relative risks for ER-/PR- breast cancer were 1.21 (0.73-2.00), 0.69 (0.39-1.23), and 0.89 (0.43-1.84) (test for trend, P = .28). The authors conclude that higher red meat intake may be a risk factor for ER+/PR+ breast cancer among premenopausal women.

The current study was designed to assess the influence of the phytoestrogens genistein and apigenin on breast cancer growth. Genistein and apigenin are present in several commercial supplements designed to be used for postmenopausal symptoms and breast health. Both flavonoids were found to stimulate proliferation of estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) MCF-7 and estrogen receptor alpha (ERα-positive) T47D breast cancer cells. However, the compounds did not stimulate the proliferation of ERα-negative MDA-MB-435 breast cancer cells. Genistein was observed to be more efficient in this regard due to its higher binding affinity for ERα. Similarly to actions previously described for estradiol (E2), both genistein and apigenin were found to down regulate ERα and enhance estrogen response element-dependent gene expression. An additional finding that genistein antagonizes the anti-proliferative effect of hydroxytamoxifen indicates that certain phytoestrogens may be detrimental for women with breast cancer who are being treated with tamoxifen. The authors conclude that because of their ability to stimulate breast cell growth, the use of phytoestrogen supplements in postmenopausal women could be detrimental.

The current study was designed to investigate the influence of oleic, linoleic and eicosapentaenoic acids on the bioavailability of β-carotene, including plasma β-carotene response and its conversion to retinol (vitamin A). The study was conducted by using single (9 hour time course) and repeated (10 days) dose administrations in rats. After a single dose, the levels of plasma β-carotene and retinyl palmitate in the oleic acid and eicosapentaenoic acid groups were higher by 13, 7 and 11, 6 folds than in the linoleic acid group (p < 0.05). The liver β-carotene level in the oleic acid and eicosapentaenoic acid groups were higher by 3 and 1.2 folds than in the linoleic acid group (p < 0.05). After 10 days' repeated dose, the plasma β-carotene and retinyl palmitate levels in oleic acid (6.2%, 51.7%) and eicosapentaenoic acid (25.4%, 17.23%) groups were higher than in the linoleic acid group (p < 0.05). The liver β-carotene level in oleic acid (21.2%) and eicosapentaenoic acid (17.6%) groups also were higher than in the linoleic acid group (p < 0.05). In both the experiments, the activity of β-carotene 15,15′-dioxygenase in the intestinal mucosa and plasma triglyceride levels were also found to be higher in the oleic acid and eicosapentaenoic acid groups than in the linoleic acid group. β-carotene excreted through the urine and feces of the oleic acid and eicosapentaenoic acid groups was lower than that of the linoleic acid group. The authors conclude that the results demonstrate an improved absorption and metabolism of β-carotene when fed a diet supplemented with oleic acid or eicosapentaenoic acid compared to linoleic acid.

The present study was designed to examine whether certain herbs alter proliferation of breast cancer cells that are estrogen receptor (ER) positive but differ in the expression of ER and ERß, and whether these herbs also alter cellular response to estradiol (E2). The breast cancer cell lines MCF-7 (60:40 ER:ERß) and T47D (33:67 ER:ERß) were treated with various strength dilutions of standard extracts of angelica (dang gui), reishi mushroom (ling zhi), licorice (gang cao), fo-ti (he show wu), and astragalus (huang qi) in the presence or absence of estradiol (1nm). Two controls were used: E2 treatment only and no treatment. The proliferation index was determined after 72 hours and values for the herbal treatments were compared to those of the controls. The MCF-7 cells were found to respond more strongly to E2 than did the T47D cells. The most noteworthy difference between these two cell lines was seen in their responses to fo-ti, reishi mushroom, and angelica. The MCF-7 cells either showed no response (fo-ti) or only a slight response (angelica and reishi mushroom) to the herbal extracts. On the other hand, the T47D cells exhibited a dose-related upswing in proliferation at higher doses of fo-ti, reishi mushroom and angelica, with the response to angelica and reishi mushroom exceeding the E2 control levels. This differential response was also found when both cancer cell lines were treated with these three herbs along with E2. In the MCF-7 cells, E2 tended to mask the effects, if any, of these herbs. In T47D cells, however, the addition of E2 to both reishi mushroom and angelica resulted in an additive effect, the proliferation index exceeding E2-stimulated levels at the higher doses. Fo-ti combined with E2 in the T47D cells was found to have no effect on E2-induced proliferation. Astragalus without E2 was found to be biphasic in both cell lines, with proliferative effects at the highest doses reaching E2 control levels in MCF-7 cells and exceeding E2 control values in T47D cells. Astragalus combined with E2 had no effect on the E2-induced proliferation in MCF-7. However, in T47D cells, astragalus plus E2 maintained a biphasic response with enhancement of proliferation at higher doses. Licorice alone showed a proliferative effect equivalent to that of the E2 control in MCF-7 cells; in T47D cells, licorice produced a strong dose response exceeding that of the E2 control. These responses did not change when E2 was added to licorice in both cell lines. These results show that some traditional Chinese medicine herbs used for immune system support may be estrogenic, and that the response differs depending on the breast cancer cell line and the presence or absence of estradiol. Generally speaking, T47D cells respond most strongly to these herbs, most likely because of their higher content of ERß, which has a higher affinity than ER for phytoestrogens. The authors conclude that the estrogenicity of these herbal preparations should be taken into account by those who want to reduce their estrogen exposure.

The current case-control study was designed to examine the relationship between alcohol consumption and the risk of the most hormonally-responsive breast cancer types (i.e., lobular or hormone receptor positive breast cancers). The study included 975 women 65 to 79 years of age diagnosed with invasive breast cancer during 1997–1999 in Washington State, as well as 1,007 controls. Ever-use of alcohol over the past 20 years was found to be associated with a 1.3-fold [95% confidence interval (CI), 1.0–1.5] increased risk of breast cancer, although this increase was mostly accounted for by women who drank at least 30.0 g per day of alcohol [OR, 1.7; CI: 1.1–2.6]. Ever-use of alcohol also was found to be associated with a 1.8-fold (CI: 1.3–2.5) increased risk of lobular cancer compared to a 1.2-fold (CI: 0.9–1.4) increased risk of ductal cancer. Ever-users of alcohol had an increase in risk of ER+/PR+ tumors (OR, 1.3; CI: 1.1–1.7), but no impact was observed for their risks of ER-/PR- or ER+/PR- breast cancer. The authors conclude that alcohol use appears to be more strongly associated with lobular and hormone receptor-positive cancers than it is with other types of breast cancer.