The present study was designed to investigate the chemopreventive activity of blueberry extract in triple-negative breast cancer. Blueberry extract was found to reduce cell proliferation in HCC38, HCC1937, and MDA-MB-231 cancer cells with no effect on noncancerous MCF-10A breast cells. Wound-healing assays and migration through a polyethylene terephthalate membrane were used to show that blueberry reduced the metastatic potential of triple negative MDA-MB-231 cells through inhibition of cell motility. Western blotting demonstrated that blueberry treatment decreased the activity of matrix metalloproteinase-9 and the secretion of urokinase-type plasminogen activator, at the same time increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium. In additional experiments, cell signaling pathways that control the expression or activation of these processes were investigated using Western blotting and reporter gene assays. Treatment with blueberry was found to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT and NFkappaB activation in MDA-MB-231 cells. However, protein kinase C and extracellular signal-regulated kinase (ERK) were not affected. In an animal model, the ability of blueberry to inhibit triple-negative breast tumor growth was evaluated using MDA-MB-231 xenografts. Tumor weight and proliferation (Ki-67 expression) were found to be lower in blueberry-treated mice, whereas apoptosis (caspase-3 expression) was higher compared with mice not receiving blueberry treatment. Immunohistochemical analysis of tumors grown in blueberry-fed mice had decreased activation of AKT and p65 NFkappaB signaling proteins, but there was no observable effect on the phosphorylation of ERK. The authors conclude that blueberry phytochemicals exert an inhibitory effect on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFkappaB pathway.

The present study was designed to investigate differences in how dietary blueberries and black raspberries may prevent breast cancer. The authors previously demonstrated that berries in the diet of ACI rats provided protection against estrogen-induced mammary tumorigenesis. In the current study, rats were administered a diet containing 5% blueberry or black raspberry two weeks before implantation with 9 mg 17β-estradiol. Rats were killed at three weeks, three months and approximately seven months (when tumor incidence in the control group that did not receive berries reached 80%). The berry diets were associated with significantly reduced (p<0.05) tumor volume (control: 801.2±105.3 mm3; blueberry: 395±97.9 mm3; black raspberry: 461±109.8 mm3) and tumor multiplicity (control: 6.9±0.9; blueberry: 4.4±0.6; black raspberry: 4.3±0.6). Importantly, while blueberry resulted in lower tumor volume than black raspberry, black raspberry was more effective in delaying the first tumor incidence, by five weeks (p<0.05). In further studies, key molecules of cell-cycle regulation, cell proliferation and transcription were investigated. Estrogen treatment up-regulated the cell-cycle regulatory molecule cyclin D1 by 3-4-fold in mammary tissues. However, cyclin D1 was significantly down-regulated by the blueberry diet as early as three weeks after estradiol implantation and remained down-regulated during the entire tumorigenesis period, as shown by Western blot analysis. On the other hand, the black raspberry diet did not result in any significant down-regulation of cyclin D1. Estrogen receptor α, which was significantly overexpressed at all three time points after estradiol administration, was significantly offset by the black raspberry diet whereas this effect was less pronounced in mice on the blueberry diet. While blueberry contains five different anthocyanidins (delphinidin, cyanidin, malvidin, peonidin, and petunidin) and insignificant levels of ellagic acid, black raspberry contains primarily the anthocyanidin cyanidin and high levels of ellagic acid. The authors conclude that the distinct and specific molecular targets and pathways involved in the protective actions of the two berries are derived from their distinct phytochemical signatures.

The present study was designed to determine the antioxidant capacity, vitamin C content, and polyphenolic compounds of black currant, blueberry, raspberry, red currant, and cranberry extracts. The antioxidant capacity was determined using the FRAP (ferric reducing ability of plasma) assay, a simple test of total antioxidant power. The vitamin C and phenolic and polyphenolic compounds contents of the berries was determined by reversed-phase HPLC-PDA-MS3 and reversed-phase HPLC-PDA with an online antioxidant detection system. A variety of anthocyanins were found to be the major contributor to the antioxidant capacity of black currants and blueberries. Lower antioxidant capacity was found for red currants and cranberries; this appeared to be due mainly to the lower anthocyanin content of these berries. Raspberries also were found to have a lower anthocyanin content than black currants and blueberries. However, this did not translate into significantly lower antioxidant capacity because raspberries contain the ellagitannins sanguin H-6 and lambertianin C. These ellagitannins were responsible for 58% of the antioxidant capacity of the raspberries. Vitamin C was responsible for 18% to 23% of the antioxidant capacity of black currants, red currants, and cranberries, as well as 11% of the antioxidant capacity of raspberries. However, the vitamin C content of the blueberry extract was not significant and did not contribute to its antioxidant capacity. The cranberry extract contained procyanidin dimers, which contributed 7% of its antioxidant capacity. However, the authors were unable to measure the contribution of polymeric proanthocyanidins to the antioxidant capacity of the five berries since they were not amenable to analysis by reversed-phase HPLC.

The study assessed the bioavailability of phenolics in humans and the associated plasma antioxidant capacity after the consumption of blueberries with and without milk. Phenolics are active compounds in plants that help give blueberries their antioxidant potential. When blueberries and milk were ingested together, there was no increase in plasma antioxidant capacity. In addition, there was a reduction in the peak concentrations of caffeic and ferulic acids in the blood, as well as a reduction in the overall absorption of caffeic acid. The authors conclude that the antioxidant properties of blueberries were reduced because of their affinity for protein.

Blueberries may inhibit the growth of common blood vessel tumors in infants and children. Feeding a blueberry extract to mice with blood vessel tumors safely decreased the size of the tumors and improved survival. The mice with blood vessel tumors that were fed the blueberry extract lived twice as long as control mice and had smaller tumors. The blueberry extract appeared to inhibit blood vessels formation and certain signaling pathways.

The apparent anti-cancer properties of black raspberries and blueberries may be in part due to the inhibition of mammary cell proliferation. Female rats prone to breast cancer were divided into four groups, each receiving either a control diet or a diet supplemented with powder of black raspberry or blueberry. Two weeks later three groups, one on the control diet and the other two on berry diets, were treated with subcutaneous estradiol implants. Three weeks after this treatment, all three groups showed increased mammary cell proliferation. However, the blueberry diet resulted in a proliferation index 66% lower than the control diet, and the index was also 32% lower in the mice fed the black raspberry diet. The authors examined whether the antiproliferative activity of the berries correlated with their bioactive contents by analyzing the total phenolic and anthocyanin contents. They found that, contrary to expectations, the black raspberry powder had a higher total phenolic content than the blueberry powder and the difference in the anthocyanin content was even greater. This suggests that other attributes or the particular combination of phytochemicals in blueberries might provide additive or synergistic benefits.

The current study investigated the ability of dietary berries and ellagic acid to reduce estrogen-mediated mammary tumorigenesis. It has been demonstrated that estrogen acts as a complete mammary carcinogen in ACI rats. This animal model enabled the researchers to perform prevention studies to identify compounds that are effective against estrogen-induced breast cancer. Eight to nine week old female ACI rats were fed either an AIN-93M diet (n = 25), or a diet supplemented with powdered blueberry (n = 19) at 2.5% wt/wt, powdered black raspberry (n = 19) at 2.5% wt/wt, or ellagic acid (n = 22) at 400 ppm. The animals received implants of 17beta-estradiol two weeks later, were palpated periodically for mammary tumors, and were euthanized after 24 weeks. No differences were found in tumor incidence at 24 weeks. However, tumor volume and multiplicity were reduced significantly after dietary intervention. Compared with the control group, ellagic acid was found to reduce mammary tumor volume by 75% (P < 0.005) and tumor multiplicity by 44% (P < 0.05). Black raspberry was almost as effective, with tumor volume diminished by > 69% (P < 0.005) and tumor multiplicity by 37% (P = 0.07). Blueberry showed a 40% reduction in tumor volume, with no significant reduction in tumor multiplicity. The authors conclude that both ellagic acid and berries are effective in the prevention of solely estrogen-induced mammary tumors.

This review discusses the effects of resveratrol, an antioxidant found in grapes and red wine, against UV radiation exposure and resveratrol's role as a sensitizer to enhance the impact of radiation treatment. UV radiation is a known cause of the majority of skin cancers and precancerous conditions such as actinic keratosis. Chemoprevention with botanical antioxidants is an approach that might be a plausible strategy for preventing sun damage, including photocarcinogenesis. Resveratol has been shown to protect against UVB exposure-related damages in vitro and in vivo. In addition, resveratrol has been shown to act as a sensitizer to enhance the therapeutic effects of ionizing radiation against cancer cells. The authors conclude that, based on the available literature, resveratrol may be useful for (1) prevention of UVB-mediated damages including skin cancer; and (2) enhancing the response of radiation therapies against hyperproliferative, precancerous and neoplastic conditions.

It has been hypothesized that fruit and vegetable intake might provide protection again estrogen-negative breast cancer but not against estrogen-positive breast cancer. The current study was to designed to elucidate a mechanism by which fruit intake might provide protection against ER-negative but not ER-positive breast cancer. ER-negative breast cancer cells have a much greater capacity than ER-positive cells to migrate, invade and proliferate at the site of metastasis. The study tested whether anthocyanin-rich fruit extracts (red grape skin, bilberry, blackberry, fermented-grape, and black currant) inhibited the motility of a highly invasive line of ER-negative breast cancer cells. All of the tested anthocyanin-rich fruit extracts were effective, however their respective potency differed markedly. The grape and bilberry extracts provided the greatest ability to inhibit the migration and invasiveness of ER-negative breast cancer cells and this protection was correlated with the dose.

Wild lowbush blueberry extract was analyzed for its chemopreventive potential by testing the ability of the component compounds to inhibit the initiation, promotion, and progression stages of cancer. The results indicate that lowbush blueberries contain a number of compounds that inhibit multiple stages of carcinogenesis, and that different types of phenolic compounds are active at different stages.

The present study investigated the effects of extracts of blueberries, black currant, black chokeberries, apple, sea buckthorn, plum, lingonberries, cherries, and raspberries on proliferation of hormone receptor positive breast cancer cells. The extracts decreased the proliferation of breast cancer cells and the effect was proportional to concentration. There were great variations in the antioxidants, cartenoids, flavonols, hydroxycinnamic acids, anthocyanins, phenolics and Vitamin C in the extracts. The antiproliferative effects correlated with levels of some carotenoids and with vitamin C levels. The same inhibition of cell proliferation could not be found using Vitamin C alone, suggesting a possible synergistic effect of Vitamin C and other substances.

Fresh juice and extracts of strawberry, blueberry, and raspberry fruits were tested for their ability to inhibit the formation of mutations by methyl methanesulfonate and benzo a pyrene, known carcinogens. All three juices significantly inhibited mutagenesis by both carcinogens. Of the extracts, the hydrolyzable tannin-containing fraction of ethanol strawberry extract was the most effective at inhibiting mutations.

The female hormone, 17ß-estradiol (E2) is a known risk factor in the development of breast cancer. In this study, female ACI rats were implanted with E2-filled silastic tubes. The rats were provided either a control diet or a diet supplemented with 2.5% powdered mixed berries (1:1 mixture of strawberries, raspberries, blueberries, blackberries and black raspberries), 2.5% blueberries, 2.5% blueberries plus ellagic acid, or ellagic acid. Compared to the control diet, the adduct (cancer-causing enzymes) levels were significantly decreased by the test diets: The P-1 adducts were reduced by >75% with blueberries and >50% each with blueberries plus ellagic acid, and ellagic acid alone. Ellagic acid was more effective (60%) in diminishing the P-2 adducts, followed by blueberries, or blueberries plus ellagic acid (30-40 %). The mixed berries, however showed no change in the adduct levels.

Food frequency questionnaires were given to 90,630 women in the Nurses Health Study II in 1991 and 1995 to evaluate the association of flavonol intake with breast cancer risk in premenopausal women who were between 26 and 46 years at baseline in 1991. During eight years of follow-up, there were 710 cases of invasive breast cancer. There were no associations seen between consumption of individual flavonols such as kaempferol, quercetin or myricetin and breast cancer risk. The multivariate RR, comparing highest to lowest quintiles of cumulative average flavonol intake, was 0.94 for sum of flavonol-rich foods. Among the major food sources of flavonols, the authors found a significant inverse association of breast cancer with intake of beans and lentils but not with tea, onions, apples, string beans, broccoli, green pepper or blueberries.

Blueberry and strawberry extracts were tested against cultures of two aggressive cervical cancer cell lines and two breast cancer cell lines. The extracts significantly decreased the growth of both cervical and hormone receptor positive breast cancer cells. Strawberry extract was more effective in decreasing the growth of breast cancer cells whereas blueberry extract demonstrated more growth inhibition of cervical cancer cells. In addition, an aqueous extract of raspberry and an ethanol extract of blueberry both were found to inhibit mutagenesis by carcinogens.