Therapeutic Potential of Vaccinium Berries in Breast Cancer: History
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Contributor:
Naser A. Alsharairi

Breast cancer (BC) is the largest contributor to cancer deaths in women worldwide. Various parts of plants, including fruits, are known for their therapeutic properties and are used in traditional medicine. Fruit species exhibit anticancer activities due to the presence of bioactive natural compounds such as flavonoids and carotenoids. The Vaccinium spp. are fleshy berry-like drupes and are rich in bioactive compounds, with flavonols, flavanols, chalcones, and phenolic acids as the major groups of compounds. While there is clear evidence linking Vaccinium berries with a decreased risk of BC both in in vivo and in vitro experiments, the exact mechanisms involved in the protective effects of Vaccinium spp. rich extracts on BC cells are not fully understood. 

  • Vaccinium spp.
  • fleshy berry fruits
  • bioactive compounds
  • breast cancer

1. Introduction

Breast cancer (BC) is regarded as the most common cancer in women globally, with an estimated 2.3 million cases and close to 700,000 deaths occurring in 2020 [1]. The burden of BC is projected to reach 3 million cases and 1 million deaths by 2040 [2]. China and South Korea had relatively low BC incidence, but showed higher mortality trends than the USA, Australia, and the UK during 2015–2020 [1]. The etiology of BC is related to many non-modifiable and modifiable risk factors. The non-modifiable factors include older age, menstrual period/menopause, pregnancy/breastfeeding, previous history of BC/radiation therapy, and non-cancerous breast diseases [3]. Smoking, alcohol intake, low physical activity, a high body mass index, hormonal replacement therapy, insufficient vitamin supplementation, ultra-processed food intake, and exposure to chemicals/artificial light also play a role in BC as modifiable risk factors [3][4]. BC is classified into four major molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor-2 (HER2)-positive, and basal-like/triple-negative (TNBC) [3][5]. Luminal A and B comprise 60% and 10% of all BC cases, respectively, and express estrogen (ER) and progesterone (PR) receptors [3][5]. The luminal A subtype, distinguished by ER+/PR+/HER2-, has lower proliferation (evaluated by Ki67 antigen expression) and better prognosis than the luminal B subtype [3][5][6]. The HER2-positive subtype, a member of the receptor tyrosine kinase family, represents about 10% of BC cases, and is characterized by the absence of ER/PR, higher HER2 expression, and is more aggressive and faster-growing than luminal cancers [3][5][7]. The TNBC subtype accounts for 20% of BC cases, and is characterized by ER-/PR-/HER2-, high expression of proliferation-related genes, an aggressive phenotype, and early relapse [3][5][8]. TNBC is further classified into six subtypes: mesenchymal (M), basal-like 1 (BL-1), basal-like 2 (BL-2), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and immunomodulatory (IM), which feature a high expression of genes associated with growth factor/cytokine signaling, cell motility, and cell differentiation/natural killer cell pathways [8].
Several preclinical and clinical trials have evaluated evidence-based treatment for BC. Neoadjuvant endocrine therapy (NET) either alone or in combination with targeted agents, such as cyclin-dependent kinase 4/6 (CDK 4/6), mammalian target of rapamycin (mTOR), and phosphatidylinositol-3 kinase (PI3K) inhibitors, has clinical benefit for patients with luminal BC [3][9][10]. Trastuzumab, tyrosine kinase inhibitors (lapatinib, afatinib, pyrotinib), P13K/serine, threonine kinase/mTOR (PI3K/AKT/mTOR), and blocking drugs (e.g., trastuzumab, everolimus, paclitaxel) are regarded as options for the treatment of HER2-positive BC [11][12]. The common treatment options of TNBC are Poly (ADP-ribose) polymerase (PARP) inhibitors (Talazoparib, Rucaparib, Niraparib, Olaparib), growth factor inhibitors (Axitinib, Afatinib, Nazartinib, Pazopanib, Bevacizumab), mTOR inhibitors (everolimus, RapaLink-1, rapamycin), PI3K inhibitors (Idelalisib), immune checkpoints (Ipilimumab, Nivolumab), and mitogen-activated protein kinase (MAPK) inhibitors (Trametinib, Dabrafenib) [13].
Fruits are categorized as fleshy or dry fruits, depending on their water content at ripening [14]. Fleshy-fruited species contain high water contents, grow in relatively low-elevation forests, and prefer evapotranspiration-shaded habitats, where plants are exposed to low wind speeds and direct sunlight, and thus attract frugivores who eat the fruits and disperse the indigestible seeds [14]. Fleshy fruits are further categorized as climacteric (e.g., banana, apple, mango, tomato) or non-climacteric (e.g., strawberry, grape, berry) based on their ethylene biosynthesis during ripening [15]. Ethylene production is increased in climacteric fruits at the onset of ripening, whereas abscisic acid (ABA) production is increased in non-climacteric fruits [16][17]. Non-climacteric fruits are also sensitive to low levels of ethylene [17][18][19]. In climacteric fleshy fruit ripening, ethylene plays a key hormonal role in stimulating the differential expression of many gene encoding transcription factors that regulate starch/pigments and carotenoid accumulation, cell wall softening, texture change and aroma, flavor, and skin color development [15][18]. Ripening is considered an important stage where many bioactive flavonoids are accumulated in fleshy fruits [19].
Vaccinium berries are considered non-climacteric fleshy fruits. The genus Vaccinium is the largest polyphyletic member of the Ericaceae family, which consists of several fruit-bearing species that generate fleshy fruits classified as berries [20]. Vaccinium spp. such as V. corymbosum L./angustifolium L. (blueberry), V. myrtillus L. (bilberry), V. uliginosum L. (bog bilberry), Arctostapylos uva-ursi L. (bearberry), V. vitis-idaea L. (lingonberry), and V. macrocarpon L./oxycoccos L. (cranberry) have been widely used as medicinal plants in Europe and Central/North America, due to the high levels of bioactive compounds present in their parts, which exert strong anti-inflammatory and antioxidant effects against some diseases, such as neurodegenerative disorders, atherosclerosis, diabetes, and cancer, as demonstrated by in vitro and in vivo studies [21][22][23][24][25][26]. Vaccinium berries were also used for treating several conditions, such as gastrointestinal disorders, respiratory system infections, hepatitis, and renal/kidney stones [25]. The types and levels of natural flavonoids vary in Vaccinium berries depending on their species, latitude, geographical origin, cultivation conditions, and ripeness stage [21]. The main bioactive compounds identified in Vaccinium berries were flavonols (quercetin, isoquercitrin, rutin, kaempferol, myricetin, isorhamnetin, syringetin), flavanols (catechin, epicathechin, epigallocatechin, proanthocyanidins, anthocyanins), chalcones, phenolic acids, and stilbene-based derivatives (e.g., piceatannol, resveratrol, pterostilbene) [21][22][23][25][27][28][29][30].
The bioavailability of bioactives in Vaccinium berries is important for evaluating their beneficial effects as potential therapeutic agents in BC. Previous intervention studies showed increases in plasma quercetin levels up to 50% in volunteers consuming a diet containing lingonberries and bilberries for 6 weeks [31]. Research evidence points to increased plasma concentrations and urinary excretions of different polyphenols (quercetin, caffeic, protocatechuic, p-coumaric, and vanillic acid) in adults consuming products prepared from lingonberries, bilberries, chokeberries, and black currants [32]. Human research has revealed high absorption of anthocyanidin peonidin glycosides and chlorogenic acids in adults consuming wild blueberries [33]. The cranberry proanthocyanidin-A2 is detected in the plasma and urine of healthy adults in very high contents after being produced from polymers/oligomers through microbiota-mediated catabolism [34]. The stability of polyphenols and anthocyanins in wild blueberries (V. angustifolium) is generally high during simulated in vitro digestion [35]. The stability of anthocyanins during in vitro digestion showed that hydrophobic anthocyanins are easier to absorb than hydrophilic anthocyanins [36]. The administration of a blueberry–grape combination to mice increases plasma flavonols, phenolic acids, and resveratrol levels [37].

2. Blueberry and Cranberry in BC Treatment

A few experiments have demonstrated the therapeutic efficacy of blueberry and cranberry extracts in BC cells. The ethanolic extracts from blueberry cultivars (Tifblue and Premier) showed an inhibitory effect on carcinogen benzo(a)pyrene-mutated BC in vitro [38]. In vitro and in vivo experiments revealed that blueberry inhibits genes involved in TNBC cell proliferation, migration, and motility, while upregulating genes involved in cell apoptosis via inhibiting the PI3K/Akt and nuclear factor kappa-B (NFκB) signaling pathways [39]. Intake of blueberry powder at a concentration of 5% inhibits TNBC cell proliferation/metastasis and influences anti-inflammatory cytokine production in mice via suppressing the Wnt/β-catenin signaling pathway. Further, blueberry powder at a concentration of 10% increases the apoptotic potential of TNBC cells [40]. Blueberry inhibits the metastasis and tumor growth of TNBC cells in Xenograft mice through increasing anti-inflammatory cytokine production [41]. The blueberry blend (Tifblue and Rubel) has shown anti-proliferative effects on 17β-estradiol (E2)-mediated BC in August-Copenhagen-Irish (ACI) rats by reducing ER-related gene expression in the mRNA/protein levels and E2-specific miRNAs [42]. Treatment with blueberry for an average of 24 weeks inhibits estrogen-induced mammary tumorigenesis in ACI rats by reducing the expression of E2-metabolizing enzymes [43].
Mice treated with either non-fermented blueberry juice (NBJ) or polyphenol-enriched blueberry preparation (PEBP) at different concentrations showed a significant inhibition of proliferation, tumor growth, metastasis, invasion, mobility, and mammosphere formation in BC cells. This was mediated by modulating the cellular signaling cascades of breast mammary cancer stem cells (CSCs), including the inhibition of the signal transducer and activator of transcription 3 (STAT3), extracellular-signal regulated kinase 1/2 (ERK 1/2), PI3K, and Akt signaling pathways, while activating the signaling pathways of mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and stress-activated protein kinase (SAPK) [44]. In vitro experiments reported a significant BC cell invasion inhibition when treated with NBJ and/or PEBP at different concentrations. This was observed through downregulating the expression of oncogenic micro (miR)-210 and neuroblastoma RAS viral oncogene homolog (NRAS), while upregulating the expression of tumor suppressor miR-145 and the forkhead box O1 (FOXO1) transcription factor [45]. Only one study showed that blueberry and cranberry suppress the proliferation of BC cells. This effect was accompanied by arresting the cell cycle at the G1 phase through downregulating cell cycle-related gene expression [46].

3. Natural Bioactive Compounds Derived from Vaccinium Berries in BC Treatment

3.1. Flavanols and Phenolic Acids

Several experiments so far showed effective results of flavanols and phenolic acids, from the most-occurring phytochemicals in blueberry, cranberry, and bilberry, in BC treatment. In vitro experiments have shown that flavanols (anthocyanins, proanthocyanidins, and catechins) extracted from cranberry press cake inhibit BC cell proliferation via the induction of cell cycle arrest in phases G1 and G2/M, leading to apoptosis [47]. The treatment of BC cells with cranberry phytochemical extracts (cyanidin, catechins, and gallic acid) demonstrated significant inhibition of proliferation, as well as the induction of apoptosis and cell cycle arrest in phases G0/G1 and G1/S in vitro [48]. Treatment with cranberry- and blueberry-derived anthocyanins inhibits BC cell proliferation at high concentrations (150 and 200 μg/mL) in vitro [49].
Blueberry anthocyanins and anthocyanin-pyruvic acid adduct extracts inhibit BC cell proliferation and invasion at a concentration of 250 μg/mL in vitro. Moreover, the anthocyanin-pyruvic acid adduct extract showed apoptotic activities in MCF-7 cells at the same concentration by increasing the activity of caspase-3 [50]. Blueberry anthocyanin extracts exert anti-proliferative effects, also in vivo, by downregulating the expression levels of cytochrome P4501A1 (CYP1A1) in BC cells [51]. Anthocyanins extracted from gardenblue blueberry in combination with the chemotherapeutic drugs cisplatin (30.45 μg/mL) and doxorubicin (6.97 μg/mL) showed anti-proliferative effects in BC cells by inducing apoptosis through decreasing DNA damage [52].
In vivo experiments in mice showed that treatment with a polyphenolic mixture derived from fermented blueberry juice and containing gallic acid, catechol, and protocatechuic acid resulted in the suppression of mammosphere formation in BC cells by increasing the expression of miR-145 and FOXO1 [53]. Blueberry phenolic acids, and hippuric acid in particular, have exerted in vivo inhibitory effects on mammosphere formation in MDA-MD-231 cells and their CD441/CD242/ESA1 subpopulation through the induction of the tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression [54].
Bilberry anthocyanin extract was shown to inhibit proliferation and induce apoptosis and G2/M-phase cell cycle arrest in MCF7-GFP tubulin cells at high concentrations (≥0.5 mg/mL) in vitro [55]. Anthocyanidin aglycone (Anthos) isolated from the standardized anthocyanin-enriched extract of bilberry has demonstrated antiproliferative and anti-inflammatory activities via the inhibition of TNFα-induced NF-κB levels in vitro and in vivo, with no toxic side effects observed against BC cells [56]. In another in vitro and in vivo study, bilberry Anthos inhibited the proliferation, viability, migration, invasion, and metastasis of BC cells through the induction of apoptosis and cell cycle arrest in phases G0/G1 and G2/M. The mechanisms underlying the effect are related to the modulation of epithelial-to-mesenchymal transition (EMT) markers and apoptosis-related proteins. Further, Anthos in combination with the paclitaxel drug inhibits tumor growth and metastasis in BC cells through the suppression of NF-kB activity [57]. Flavanol- and phenolic acid-rich extracts of the bilberry showed antimicrobial effects in BC cells in vitro through inhibiting the growth of Escherichia coli (E. coli) and Salmonella typhimurium (S. typhimurium) strains [58].

3.2. Stilbene-Based Derivatives

Stilbene-based derivatives, including pterostilbene, piceatannol, and resveratrol, isolated from Vaccinium berries (blueberry, cranberry, bilberry, and lingonberry) have been demonstrated to have anti-BC effects. In vitro experiments using BC cells showed an inhibition of viability, and an induction of apoptosis and S-phase arrest after treatment with pterostilbene via increasing mitochondrial depolarization, superoxide anion, and caspase-dependent apoptosis in the cell cycle [59]. Pterostilbene in combination with tamoxifen, a nonsteroidal antiestrogen, showed anti-viability and apoptotic activities in BC cells at different concentrations in vitro [60]. Pterostilbene exerts proliferation, invasion, and viability inhibitory effects on BC cells in vitro, as indicated by decreasing heregulin-β1 (HRG-β1)-mediated matrix metalloproteinase-9 (MMP-9) expression through the suppression of the PI3K/Akt and p38 kinase signaling pathways [61]. Pterostilbene treatment was shown to suppress the in vitro and in vivo proliferation activities of BC cells by inducing apoptosis through the inhibition of the expression of ER-α36 and the MAPK/ERK and PI3K/Akt signaling pathways [62].
Pterostilbene enhances the in vitro apoptosis activities in tumor necrosis factor-related apoptosis-induced ligand (TRAIL)-resistant TNBC cells through the activation of the reactive oxygen species (ROS)-mediated p38/C/EBP-homologous protein (CHOP) signaling pathway, leading to death receptors and pro-apoptotic gene expression [63]. Pterostilbene has been reported in vitro and in vivo to inhibit tumor-associated macrophage (TAM)-induced invasive/metastatic potential and cancer stem cell (CSC) generation through the suppression of the NFκB signaling pathway and EMT-related molecules [64]. Pterostilbene showed strong antiproliferative activities and an induction of apoptosis and G0/G1-phase arrest both in vitro and in vivo. These effects occur in BC cells through the activation of pro-apoptotic molecules and the inhibition of signaling/anti-apoptotic molecules [65]. Treatment with pterostilbene suppresses proliferation, along with the stimulation of apoptosis and cell cycle arrest in phases G1 and G2/M in vitro. These effects are triggered by downregulating human telomerase reverse transcriptase (hTERT) through inhibiting cMyc expression and reducing telomerase levels in BC cells [66].
Piceatannol was reported to induce anti-migration, anti-invasion, and anti-adhesion activities in vitro by inhibiting MMP-9 expression and the PI3K/AKT/NF-κB signaling pathway in BC cells [67]. Treatment with resveratrol in combination with paclitaxel both in vitro and in vivo showed an inhibition of viability, along with the stimulation of apoptosis and S-phase cell cycle arrest in BC cells. This is mediated through reducing the accumulation of intracellular ROS and the expression of anti-apoptotic molecules [68]. The treatment of BC cells with resveratrol resulted in the inhibition of cell viability and the induction of cell apoptosis and G1-phase cell cycle arrest in vitro. This is triggered by the inhibition of the PI3K/Akt/mTOR signaling pathway, fatty acid synthase (FASN), cyclin D1, Akt phosphorylation, and the activation of PTEN and polyomavirus enhancer activator 3 (PEA3) expression [69].

This entry is adapted from the peer-reviewed paper 10.3390/plants13020153

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