Edited by: Igor Pogribny, National Center for Toxicological Research, USA
Reviewed by: David Lin, Cornell University, USA; Jovanny Zabaleta, Louisiana State University Health Sciences Center, USA
Specialty section: This article was submitted to Nutrigenomics, a section of the journal Frontiers in Nutrition
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Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea, and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of non-coding RNA levels. Since it has been shown that non-coding RNAs such as microRNAs and long non-coding RNAs are aberrantly expressed in cancer, and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator non-coding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the non-coding RNA level.
Current research provides evidence for the importance of nutrition in terms of health and disease prevention via phytochemicals and their modes of action. Studies on the “epigenetic diet” have revealed that the consumption of soy, curry spices, red grapes, as well as blueberries has beneficial effects on the prevention of diseases like cancer (
Since miRs can either modulate or serve as tumor suppressors or oncogenes, two scientific approaches toward targeting cancer are under current investigation. One approach is to utilize miRs such as let-7, miR-34, and miR-29 in patients for anticancer therapy. The other is employing miR levels as biomarkers to diagnose, classify, and predict the clinical outcome of cancer patients. Due to the fact that circulation of miRs in blood, milk, urine, and various other body fluids has been frequently proven, their employment as biomarkers is self-evident (
The genesis of miRs is a multistep process and eventually leads to the alteration of protein levels by RNA silencing. During this process, RNA polymerase II transcribes the primary transcript, pri-miR, from inter-or intragenic regions. The recognition and cleavage of the primary transcript through Drosha, the microprocessor complex and DiGeorge critical region 8 (DGCR8), follows thereafter (
The RISC, consisting of the transactivation-responsive RNA binding protein and the catalytic component Argonaute, elicits its action by complementary binding of the 3′UTR mRNA target through the incorporated miR. Either translational repression or mRNA cleavage results from mRNA recognition by the RISC. In case of inaccurate complementary binding, translational repression occurs, whereas in the case of accurate complementarity mRNA cleavage is brought about by Argonaute. Subsequently, a decrease in protein levels is effectuated (
Tumor tissue miRs are commonly studied because particular expression patterns can be related to certain phenotypes and cancer properties. However, the miR pattern is unique to the cancer type in general as well as to the individual cancer tissue, hence, making broad generalizations is met with challenges. This also indicates that the same miR may act as tumor suppressor in one cancer type, whereas it may act as an oncogene in another. An epitome of this concept is miR-93. While being overexpressed in many cancer cases, miR-93 has also been found to have tumor suppressor properties. In less differentiated BCs, increased miR-93 expression halts tumor development and metastasis; whereas its up-regulation in more differentiated tumors was observed to result in an augmented stem cell population (
Taken together, miRs act in complex biological networks that are not yet fully understood, nevertheless, comprehending these networks and their contribution to emerging female cancers is of great importance. When administering chemotherapy, the different miR profiles of female cancers have to be taken into account as there have been indications of the impact of miRs on the response to treatment, especially on drug resistance (
According to Cancer Research UK, BC is the second leading cause of death among cancer cases. While the most common BC is ductal carcinoma, variable factors including environmental, lifestyle, and genetic factors are associated with BC risk. Despite the exposure to Bisphenol A (BPA) as well as age factors, the National Cancer Institute specifies that the risk of developing BC is critical to the inheritance of BRCA1 or BRCA2 mutations, as 55% of women are carriers of those altered tumor suppressor genes and will develop BC. In this connection, miR-146a and miR-146b-5p were discovered to influence BRCA1 by down-regulating it in sporadic triple negative breast cancer (TNBC) (
In correspondence with the specific BC subtypes, distinct miR patterns that made it possible to distinguish between basal and luminal subtypes in an independent subset of data were reported (Table
Cancer type | miR | Regulation | Indications | Diagnostic, predictive, prognostic markers | Reference |
---|---|---|---|---|---|
BC | miR-9 | ↑ N-Myc and c-Myc induced miR expression | Targets E-cadherin, thus facilitating migration and invasion | Local recurrence and estrogen receptor status | ( |
miR-17-92 cluster | ↑ Myc binds to E-box of first intron of miR-17-92 gene | Amplified in BC | Pancreatic cancer (miR-18); CLL (miR-20a); significantly higher expressed in grade 3 basal-like BC | ( |
|
miR-93 | ↑ | Halts tumor development in less diff. BC; in more diff., tumors increase in BCSC | Highly expressed in high grade tumors; differentiation between cancer and cancer-free controls | ( |
|
let-7 | ↓ Wnt-β-catenin pathway represses let-7 expression by transactivating Lin28 | let-7 family members target large gene quantity; let-7a suppresses migration and invasion of BC by down-regulating C–C chemokine receptor type 7 | Down-regulated in BC with high proliferation index/lymph node metastasis | ( |
|
miR-200c | ↓ | Targets BMI1, suppresses clonal expansion of cancer cells and formation of mammary ducts by normal mammary stem cells; tumor formation, inhibits metastasis of BC through targeting HMGB1; positive impact on Dicer levels | BC progression | ( |
|
miR-221/222 cluster | ↑ | miR-221 facilitates tumorigenesis in TNBC; miR-221 targets p27 | miR221/222 induced repression of Dicer in ERα− BC, ERα status linked to miR221/222 cluster | ( |
|
miR-146a, miR-146b-5p | ↑ | Decrease |
miR-146a levels sigificantly increased in plasma of BC patients; basal-like breast tumours decreasedly epxress |
( |
|
miR-34a | ↓ | Suppresses proliferation and migration of BC by decreasing levels of Bcl-2 and SIRT1 | Poor prognosis demonstrated in three independent cohorts of primary BC | ( |
|
miR-21 | ↑ | Correlated with advanced clinical stage, lymph node metastasis, and poor prognosis | Serum miR-21 high diagnostic accuracy for BC patients | ( |
|
miR-155 | ↑ | Overexpression is associated with metastasis | Poor prognosis | ( |
|
miR-497 | ↓ | Inhibts cell growth, migration, and invasion; targets cyclin E1 | Associated with higher differentiation grade, positive HER-2 expression, higher incidence of lymph node metastasis, and advanced clinical stage | ( |
|
miR-205 | ↓ In TGF-β or Pez induced cells that consequently were subjected to EMT | EMT by targeting ZEB1 and SIP1; targets also ERBB2 and VEGF-A; directly targets HER3 receptor and inhibits the activation of the downstream mediator AKT | miR-205 reduced in tumor probes compared to according normal probes of mammary ducts and lobules | ( |
|
miR-210 | ↑ Induced by hypoxia (HIF and VHL) | Involved in hypoxia pathway | Predictive effect on poor survival; higher risk of recurrence and metastasis, thereunder ER−, lymph-node negative cancers | ( |
|
OC | miR-9 | ↓ | Inhibits talin 1/FAK/AKT pathway; sensitises ovarian xenograft tumors to cisplatin and PARP inhibitors | Acts as tumorsuppressor in recurrent OC | ( |
miR-497 | ↓ | Represses pro-metastatic factor SMURF1 | Shorter overall survival in patients with serous cystadenoma | ( |
|
miR-21 | ↑ Increased via JNK-1/c-Jun pathway in cisplatin resistant OC cell lines | Targets PDCD4, induces cell growth, inhibition of miR-21 leads to apoptosis and chemosensitivity in OC; miR-21-3p increases cisplatin resistance thorugh targeting NAV3 in OC cell lines | NAV3 is repressed in OC tumors resistant to platinum treatment | ( |
|
let-7 family | ↓ ↑ | Let-7g sensitises ADR-RES cells to taxol/vinblastine by down-regulating IMP-1 and MDR1; let-7 targets HMGA2 | Increased expression of let-7b correlated with poor prognosis in high grade serous OC; in further study of serous OC, decreased let-7b expression was associated with poor prognosis; loss of let-7 expression in less differentiated cancer types | ( |
|
miR-200s | ↓ ↑ | PTEN repression, proliferation, metatstasis |
Low miR-200c is associated with poor prognosis | ( |
|
miR-221 | ↑ | Represses p27 and p57 | Serum miR-221 up-regulated in EOC patients | ( |
|
miR-27a | ↑ In ALDH1+ and chemoresistant cells | Associated with chemoresistance | High in a patient subgroup with very poor prognosis | ( |
|
miR-210 | ↑ In response to hypoxia; up-regulated upon VHL inactivation | Facilitates tumor growth through targeting PTPN1 and repressing apoptosis |
n/a | ( |
|
miR-145 | ↓ | Targets Sp1 and Cdk6, sensitizes OC to Paclitaxel; overexpression is linked to inhibition of proliferation, invasion, and apoptosis | OC patients have low levels of miR-145 in serum and tissue | ( |
|
miR-205 | ↑ | Facilitates proliferation and invasion of OC | Together with CA-125 and let-7f, high diagnostic accuracy for EOC; elevated plasma levels in cancer patients versus control patients | ( |
|
miR-214 | ↑ | Targets p53/Nanog axis in OC stem cells; targets PTEN thus inducing cell survival/cisplatin resistance; suppresses RNF8 | Presence of miR-214 in exosomes as well as in according tumor samples | ( |
|
UC | miR-205 | ↑ | Targets PTEN, inhibits apoptosis | Patients with decreased miR-205 expression showed better survival compared to patients with a high miR-205 level | ( |
miR-34a | ↑ In uterine leiomyoma and endometrioid endometrial adenocarcinoma | Inverse correlation between L1CAM and miR-34a levels in endometrial cancer cell lines | Primary tumor sections with increased L1CAM expression showed decreased miR-34a expression; overexpression in endometrioid endometrial adenocarcinoma linked to tumor progression and lymph node involvement | ( |
|
miR-200 family | ↑ | 200b up-regulates |
Compared to normal endometrium, in all EAC stages examined increased; combination of miR-205 and miR-200a predicted relapse; miR-200c ranked prognostic marker for overall survival of endometrioid endometrial carcinoma patients; SNP (rs1045385) possible prognostic marker for cisplatin treatment, as miR binding to AP-2α reduced | ( |
|
miR-21 | ↑ | Targets PTEN protein expression, thus affecting proliferation | Up-regulated in uterine leiomyoma cohorts, however, n/a for UC patients | ( |
|
miR-503 | ↓ | Targets cyclin D1 | Patients with relatively higher level improved survival | ( |
|
miR-199a-3p, miR-199b | ↓ | Target mTOR | miR-199b may serve as marker for EEC | ( |
|
CC | miR-145 | ↓ Expression p53 dependent in HPV+ CC cells | Suppresses p53 inhibitors and impedes invasion of HPV+ CC cells | Possibility in employment as prognostic marker; decrease linked to aggressiveness and poor prognosis | ( |
miR-375 | ↓ | Suppresses cell migration and invasion via targeting SP1 in CC cell lines | Marginal trend observed that miR-375 expression is elevated in chemotherapy resistant patient samples, further samples needed; association with drug sensitivity in BC observed as well | ( |
|
miR-181b | ↑ | AC9 is targeted directly by miR-181b, promotes proliferation, and inhibits apoptosis | Further samples needed to verify elevated miR-181b as a marker | ( |
|
miR-143 | ↓ | Targets Bcl-2 abrogates tumor development suppresses apotosis | No link to histology found in samples; clinical application researched | ( |
|
miR-126 | ↓ | Up-regulation increases sensitivity to bleomycin targets ADM | Found in serum, correlated with FIGO stage, histological grade, lymphatic invasion, distant metastasis; miR-targeting therapeutic under investigation | ( |
|
Let-7 family | ↓ | Targets HAS2 linked to cell survival, invasion | In comparison to normal tissue, cell lines displayed let-7b/c ↓; validation on tumor samples needed | ( |
|
miR-100 | ↓ | Targets PLK1 protein | In high-grade cervical lesions and CC, miR-100-PLK1 axis not as distinct, hence this correlation may occur relatively late in cervical tumorigenesis | ( |
|
miR-20a | ↑ | Cell proliferation, migration, and invasion targets TNKS2 | Lymph node metastasis, histological grade and tumor diameter | ( |
|
miR-21 | ↑ | Targets CCL20, PDCD4 stimulation of cell growth | High in serum of CC patients; miR-targeting therapeutic under investigation | ( |
|
miR-29, 29a | ↓ | Targets HSP47, increases p53 protein level when transfected into HeLa cells, inhibits migration and invasion | miR-29 is connected to HPV infection, further research necessary | ( |
|
miR-200a | ↓ | Impacts regulation of cell adhesion | Based on miR-200a and miR-9, two groups with significantly different overall survival rates could be established; indication for miR-200a delivery in patients | ( |
Although multiple research groups have studied diet and dietary patterns in correlation to female cancers, many lack investigations on the miR level. In 2014, a study on the Mediterranean diet versus the Western diet and their implications on BC risk was conducted. It implied that the consumption of vegetables and fruits has a protective effect on TNBC cancer patients. Deciphering the link between diet patterns and tumors of HER2-status, the study was the first to report that the Mediterranean diet had a strong protective impact on TNBC. Furthermore, the positive correlation between a Western dietary pattern and BC risk in general, especially in premenopausal women, was implied (
There are three general subgroups of ovarian cancer (OC), germ cell, stromal, and epithelial tumors, with the latter being the most prominent. A common feature of OC is a disease relapse within 2 years (
Especially in terms of OC with its unspecific symptoms, reliable prognostic and predictive biomarkers are avidly sought for. While prognostic markers specify the likely outcome of a disease when the patient is untreated, predictive biomarkers help to determine the patient who will most likely respond and thus benefit from the therapy (
Similar to BC, where the tumorsuppressor miR-497 has been reported to target cyclin E1, and low BRCA1 expression augmented the incidence risk, miR-479 and BRCA1 are altered in OC as well. In OC cell lines (OVCAR-3, SK-OV-3, HO-8910, HO-8910PM) as well as serous cystadenoma specimens, a decline in miR-497 expression was observed. Patients with serous cystadenoma were shown to have a correlation between miR-497 down-regulation, higher expression of the pro-metastatic factor SMURF1, and shorter overall survival. This suggests that restoration of miR-497 levels may impede OC metastasis (
While miR-9 has been associated with tumor cell motility and metastasis in BC, its function as tumorsuppressor-miR through inhibiting the talin1/FAK/AKT pathway has been described in OC (
When it comes to dealing with different miR signatures, there are not only varying patterns between EOC subtypes but also between primary tumors and their metastases. A study by Vaksman et al. was the first to prove that miR signatures are variable depending on the tumor progression status. They characterized three different sets of miRs that were highly expressed; the first one was overlapping in primary carcinomas and effusions, the second was overexpressed in primary carcinomas, and the last in effusions (
Uterine cancer (UC) is subdivided into endometrial cancer and uterine sarcoma. Endometrial cancer is rather common among Caucasian women, whereas African American women have a higher risk of fatality due to endometrial cancer (
Most cervical cancers (CC) are squamous cell carcinomas and begin in the majority of cases in the transformation zone, mostly caused by human papilloma virus (HPV) (
The emerging role for miRs as gene network regulators may facilitate the classification of different tumor phenotypes revealing new possible targets and therapies for patients. Table
As measured by the publications of articles and books, the awareness of the importance of a balanced nutrition emerges worldwide. Yet, there is comparatively little known about the impact of compounds contained in a healthy diet on miR profiles. Many of those compounds have anticancer as well as other beneficial impacts such as anti-inflammatory, anti-microbial, or anti-oxidative that are empowered to reduce mortality (
There is a plethora of phytochemicals, which have an impact on epigenetic processes such as DNA methylation, histone modifications, and non-coding RNA (Figure
Aside from quantity of foods containing chemopreventive compounds, the quality of these foods appear to be effectual as well. Compelling results were generated by Zhang et al. suggesting that horizontal miR transfer from plants to humans is possible. To be precise, miR-168a, abundant in rice, was found to be enriched in the sera of Chinese probands (
Phytochemical | Cancer model | miR regulation |
Effects | Reference |
---|---|---|---|---|
Curcumin | OC SKOV3 | miR-9 ↑ | Apoptosis by inhibiting activation of AKT and FOXO1 | ( |
BC MCF-7 stimulated with BPA | miR-19a ↓ | Modulates PTEN/AKT/p53 axis in favor of stopping proliferation and cell cylce progression | ( |
|
miR-19b ↓ | ||||
BC MCF-7, SKBR-3, Bcap-37 | miR-15a ↑ | Bcl-2 down-regulation | ( |
|
miR-16 ↑ | Induction of apoptosis | |||
BC MDA-MB-231 | 181b ↑ | Down-regulates MMP-1, MMP-3, CXCL1 and -2 | ( |
|
miR-452-3p ↑ | Inhibition of NFκB activation | |||
miR-483 ↑ | ||||
miR-423 ↑ | ||||
miR-296 ↑ | ||||
miR-181d ↑ | ||||
miR-498 ↑ | ||||
miR-320 ↑ | ||||
miR-373-3p ↑ | ||||
miR-519e-3p ↑ | ||||
let-7e ↓ | ||||
let-7c ↓ | ||||
miR-503 ↓ | ||||
Curcumin in combination with Emodin | BC MDA-MB-231 and MDA-MB-435 | miR-34a ↑ | Bcl-2 and Bmi-1 down-regulation | ( |
Inhibiting proliferation, increasing apoptosis | ||||
Genistein | BC MDA-MB-435, Hs578t | miR-155 ↓ | Up-regulates PTEN, FOXO3, CK1α, p27 | ( |
Cell growth ↓ | ||||
Apoptosis ↑ | ||||
OC SKOV3 | miR-27a ↓ | Sprouty2 mRNA and protein ↑ | ( |
|
Proliferation ↓ | ||||
Migration ↓ | ||||
OC UL-3A | miR-135 ↑ | ERα and ERβ ↑ | ( |
|
miR-765 ↑ | Migration ↓ | |||
miR-122a ↑ | ||||
miR-137 ↑ | ||||
miR-196a ↑ | ||||
miR-204 ↑ | ||||
miR-206 ↑ | ||||
miR-217 ↑ | ||||
miR-331 ↑ | ||||
miR-449b ↑ | ||||
miR-454 ↑ | ||||
miR-501 ↑ | ||||
miR-515 ↑ | ||||
miR-578 ↑ | ||||
OC UL-3B | miR-135 ↑ | ERα and ERβ ↑ | ( |
|
miR-765 ↑ | Migration ↓ (lower as in UL-3A) | |||
miR-517c ↑ | ||||
miR-7 ↑ | ||||
Resveratrol | BC MDA-MB-231-luc-D3H2LN | miR-141 ↑ | Inhibits BC invasion and CSC phenotype, resveratrol induces Ago2 expression thus promoting RNAi | ( |
miR-200c ↑ | ||||
miR-26a ↑ | ||||
miR-34a ↑ | ||||
miR-125a-3p ↑ | ||||
miR-126 ↑ | ||||
miR-128 ↑ | ||||
miR-185 ↑ | ||||
miR-193b ↑ | ||||
miR- 195 ↑ | ||||
miR-196a ↑ | ||||
miR-335 ↑ | ||||
miR-340 ↑ | ||||
miR-497 ↑ | ||||
Putative oncomiRs: | ||||
miR-378-3p ↑ | ||||
miR-10b ↑ | ||||
miR-132 ↑ | ||||
miR-222 ↑ | ||||
BXC MCF-10A | miR-16 ↑ | n/a | ( |
|
BC MDA-MB-231-luc-D3H2LN | miR-143 ↑ | |||
BC MCF-7 | ||||
BC MCF-7ADR | ||||
BC ACI rats | miR-10a (↑) | Inverse correlation of miR-129, -204, -489, and DNMT3b in normal tissue; in tumor tissue, miR-489 and DNMT3b inversely correlated Resveratrol led to demethylation of |
( |
|
miR-10b (↑) | ||||
miR-21 ↑ | ||||
miR-129 ↑ | ||||
miR-204 ↑ | ||||
miR-489 ↑ | ||||
BC MCF-7 | miR-663 ↑ | Retardation of cell division | ( |
|
miR-744 ↑ | eEF1A2 mRNA and protein expression, thus silencing of EEF1A2 | |||
DIM | BC MCF-7 | miR-21 ↑ | Cell cycle arrest, down-regulation of Cdc25A | ( |
ER or p53 genotype seem crucial for DIM induced miR-21 ↑ | ||||
DIM and Herceptin | BC SKBR3 | miR-200a ↑ | FoxM1 ↓ pAKT ↓ | ( |
miR-200b ↑ | NFκB p65 ↓ | |||
miR-200c ↑ | ||||
BC MDA-MB-468 | miR-200a ↓ | Cytotoxicity | ( |
|
miR-200b ↓ | FoxM1 ↓ | |||
NFκB p65 ↓ | ||||
Sulforaphane | BC MCF10DCIS stem-like cells | miR-140 ↑ | Colony/mammosphere formation ↓ | ( |
miR-21 ↑ | ALDH1 and expression SOX9 ↓ | |||
miR-29 ↓ | Differetial miR pattern in exosomes | |||
I3C | MCF-7, MCF10A as control | mir-34a ↑ | Cell-cycle arrest, p53 dependent CDK4 suppression | ( |
Polyphenon-60 | BC MCF-7 | let-7a ↑ | Inhibits cell growth | ( |
miR-107 ↑ | ||||
miR-548m ↑ | ||||
miR-720 ↑ | ||||
miR-1826 ↑ | ||||
miR-1978 ↑ | ||||
miR-1979 ↑ | ||||
let-7c ↓ | ||||
let-7e ↓ | ||||
let-7g ↓ | ||||
miR-21 ↓ | ||||
miR-25 ↓ | ||||
miR-26b ↓ | ||||
miR-27a/b ↓ | ||||
miR-92a ↓ | ||||
miR-125a-5p ↓ | ||||
miR-200b ↓ | ||||
miR-203 ↓ | ||||
miR-342-3p ↓ | ||||
miR-454 ↓ | ||||
miR-1469 ↓ | ||||
miR-1977 ↓ | ||||
Suppresses: | ||||
miR-30b-3p | ||||
miR-29a | ||||
miR-221 | ||||
miR-936 | ||||
miR-1249 | ||||
miR-200a | ||||
miR-424 | ||||
Pomegranate polyphenols | BC BT-474 | miR-155 ↓ | Cancer cell-specific growth suppression | ( |
BC MDA-MB-231 | miR-27a ↓ | SHIP-1 ↑ | ||
BC BT474 xenografts in nude mice | ZBTB10 ↑ | |||
Sp1, Sp3, and Sp4 ↓ | ||||
PI3K-dependent pAKT ↓ | ||||
Ellagic acid | ACI rat model | miR-122 ↑ | ERα ↓ | ( |
miR-127 ↑ | Bcl-2 ↓ | |||
miR-182 ↓ | Bcl-w ↓ | |||
miR-183 ↓ | cyclin D1 ↓ | |||
miR-206 ↑ | cyclin G1 ↓ | |||
miR-375 ↓ | FOXO1 ↑ | |||
FOXO3a ↑ | ||||
RASD1 ↑ | ||||
Betulinic acid | MDA-MB-231 xenograft | miR-27a ↓ | Abrogation of proliferative, angiogenic phenotype: repression of survivin, Sp 1, 3, 4, VEGF and VEGFR Myt-1 ↑ and thus cell cycle arrest at G2/M (pcdc2) | ( |
ZBTB10 ↑ in lungs of mice β2-microglobulin ↓ | ||||
MDA-MB-231 xenograft in nude mice | miR-106a ↓ | ZBTB4 ↑ | ( |
|
miR-106b ↓ | Sp1, Sp3, Sp4 ↓ | |||
miR-20a ↓ | EZH2 ↓ | |||
BC BT474 | miR-27a ↓ | Effects of betulinic acid CB1 and CB2 receptor dependent: | ( |
|
BC MDA-MB-453; both overexpressing ERBB2 | Sp1, Sp3, Sp4 ↓ | |||
YY1 ↓ | ||||
ERBB2 ↓ | ||||
ZBTB10 ↑ | ||||
ACA | CC Ca Ski, CC HeLa | miR-629 ↑ | Abates cellular gluthatione levels | ( |
miR-487a ↑ | ||||
miR-483-3p ↑ | ||||
miR-376a ↑ | ||||
miR-342-3p ↑ | ||||
miR-212 ↑ | ||||
miR-1262 ↓ | ||||
miR-875-3p ↓ | ||||
miR-517 ↓ | ||||
miR-411 ↓ | ||||
ACA and Cisplatin | CC Ca Ski, CC HeLa | miR-922 ↑ | ACA enhances cisplatin efficacy by preventing its inactivation if administered |
( |
miR-744 ↑ | ||||
miR-523 ↑ | ||||
miR-210 ↑ | ||||
miR-138 ↑ | ||||
miR-1271 ↓ | ||||
miR-224 ↓ | ||||
miR-21 ↓ | ||||
Garcinol | BC MDA-MB-231 | miR-200b ↑ | Induction of apoptosis and MET | ( |
BC BT-549 | miR-200c ↑ | NFκB p65 ↓ | ||
let-7a/e/f ↑ | Inhibition of Wnt signaling (nuclearβ-catenin ↓) | |||
Vimentin ↓ | ||||
ZEB-1 ↓ | ||||
ZEB-2 ↓ | ||||
E-cadherin ↑ | ||||
Glyceollins | BC MDA-MB-231 | miR-181 c/d ↑ | Apoptosis | ( |
BC MDA-MB-468; | miR-22 ↑ | repression of SLC7A11 | ||
xenografts | miR-26b ↑ | |||
miR-29b/c ↑ | ||||
miR-30d ↑ | ||||
miR-34a ↑ | ||||
miR-195 ↑ | ||||
miR-663 ↑ | ||||
miR-193a-5p ↓ | ||||
miR-197 ↓ | ||||
miR-224 ↓ | ||||
miR-486-5p ↓ | ||||
miR-542-5p ↓ | ||||
Matrine | BC MCF-7 | miR-21 ↓ | miR-21/PTEN/AKT axis targeted: | ( |
pAKT ↓ | ||||
pBAD ↓ | ||||
p21 ↑ | ||||
p27 ↑ | ||||
Artemisinin and artesunate | MCF-7, T47D | Mir-34a ↑ | Cell-cycle arrest, p53 independent CDK4 suppression | ( |
Ascorbic acid | BXC MCF-10A, | miR-93 ↓ | NRF2 and NRF2 related genes ↑ | ( |
BC T47D | MCF-10A: decrease in colony and mammosphere formation | |||
Calcitriol | OC OVCAR3 | miR-498 ↑ | hTERT mRNA stability ↓ | ( |
[OC A2780, OC A2780-CP, OC C13] | ||||
Calcifediol | BXC MCF10A | miR-182 ↓ | Protection of BXC from oxidative/low serum/hypoxia stress | ( |
BXC MCF12F | suppression of cell proliferation |
Curcumin can be obtained from the yellow rhizome of
Owing to its broad range of palliative features, curcumin targets various members of cellular signaling pathways. Not only does it play a role in the activation of the ambivalent transcription factor Nrf2 but it also impacts NFκB, AKT, FOXO1, PTEN, p53, and various other members of signaling pathways (
A further pathway targeted by curcumin is PTEN/AKT/p53 in BC. This was discovered by a study in 2014 examining the impact of curcumin on BPA on stimulated MCF-7 BC cells. As mentioned earlier, BPA is closely connected to mastocarcinoma because it acceleratedly impairs proliferation and apoptosis pathways. In this study, miR-19, a member of the miR-17-92 cluster, was recognized to be up-regulated upon BPA stimulation, leading to a decreased expression of PTEN and p53 in addition to increased levels of p-AKT, p-MDM2, and PCNA. Curcumin treatment, however, compromised BPA-induced proliferation and cell cycle progression through modulation of miR-19a and miR-19b (Figure
Curcumin acts as an anti-inflammatory agent and because chronic inflammation is a considerable risk factor for metastasis, the impact of curcumin on the miR-dependent regulation of the proinflammatory cytokines CXCL1 and -2 was examined. This was done by assessing miR expression with microarrays in the TNBC cell line MDA-MB-231 as well as in primary ER+, HER2-breast tumor samples. Hereby, 3 miRs were decreased and 10 miRs increased at least 2.5-fold in response to curcumin dosage of 25 μM (Table
Bcl-2 is a key oncogene since it can alter mitochondrial permeability and cytochrome c release, thus it can favor cell survival. Due to the fact that it is overexpressed in numerous cancer types, including female cancers, finding phytochemicals which target Bcl-2 is advantageous. Yang et al. depicted a curcumin-dependent apoptosis in MCF-7 cells through down-regulation of Bcl-2 effectuated by increased miR-15a and miR-16 levels. Other BC cell lines, namely SKBR-3 and Bcap-37, showed similar results after the administration of 60 μmol/L curcumin (
Moreover, curcumin has been proven to alter miR profiles in various other cancer types such as pancreatic, prostate, colorectal, and bladder cancer to name a few. Interestingly, several of the currently described miRs targeted by curcumin in these cancers are known to be dysregulated in female cancers as well. One prominent example is the let-7 family and its down-regulation in a diverse range of cancer types (
In the context of nutrition, BC treatment, and chemotherapy, a striking discovery has been made. Somasundaram et al. observed antagonistic effects between curcumin and chemotherapeutic agents in MCF-7, MDA-MB-231, and BT-474 human BC cells, with an inhibition by up to 70%. This was verified in an
In conclusion, curcumin or its analogs are capable of altering miR signatures in female cancers (Figure
The consumption of soy products has gained significance due in part to epidemiological studies indicating increased breast and prostate incidences in the Western world in contrast to Asia, where a soy-based diet is typically consumed. Genistein, a predominant soy isoflavone, is known to impact cancer cell proliferation, angiogenesis, induction of differentiation by directly targeting molecular signaling pathways like NFκB and AKT, as well as modulating epigenetic events, especially DNA methylation. While curcumin has low bioavailability, this is not the case for genistein: a soy-rich diet results in a noticeable plasma level of genistein (
In prostate cancer, a mix of isoflavones containing 70.5% genistein were shown to demethylate promoters of miRs acting against tumor invasion and proliferation (e.g., miR-29a and miR-1256). However, in female cancers, genistein holds an ambivalent role, specifically in BC (
Probably due to its pleiotropic effects, little information on the effect of genistein on miR levels in BC has been published. In MDA-MB-435 and Hs578t BC cells, however, genistein was found to inhibit the expression oncomiR-155 while up-regulating its targets such as PTEN, FOXO3, CK1α, and p27 at low physiological concentrations (
Aside from the limited findings with respect to genistein altered miR levels in BC, Xu et al. reported an overexpression of miR-27a in 20 FFPE ovarian tissue samples. This overexpression was abrogated upon 50 μM genistein treatment in SKOV3 OC cells, followed by a significant increase in mRNA and protein level of the putative target of miR-27a, Sprouty2. Sprouty2, an intracellular regulator of receptor tyrosine kinase signaling associated in processes like cell growth and differentiation, is a target gene of the Wnt/β-catenin pathway. Interestingly, Sprouty2 is up-regulated in the majority of colon carcinomas, while an increase in the SKOV3 cell line seems to be favorable (
It has been reported that genistein significantly reduces invasive traits and modifies miR profiles in cell lines derived from a patient with papillary serous adenocarcinoma of the ovary. Compared to the cell line UL-3A, which was collected and cultured at diagnosis, UL-3B cells were isolated after 6 months of failed treatment with Cisplatin/Paclitaxel. Differential expression of miRs after genistein treatment was observed in both cell lines: miR-135 and miR-765 levels were increased (Figure
Isoflavones, genistein in particular, were indicated to have positive effects on endometrial carcinogenesis in a mouse model as well as TNBC (
Resveratrol (trans-3, 4′, 5-trihydroxystilbene) is a natural bioactive polyphenol found in red grapes, peanuts, and blueberries for instance. It exhibits a plethora of physiological properties such as anti-oxidant, anti-inflammatory, and anti-cancer by altering cell signaling such as up-regulating the expression of Bax, PUMA, Bim, p53 and down-regulating Bcl-2, Bcl-XL, as well as survivin. Furthermore, resveratrol can cause cell cycle arrest at G1 and G1/S phases through the induction of the expression of CDK inhibitors leading to growth inhibition accompanied by apoptosis. In MCF-7 BC cells, the modulation of phosphorylated AKT and caspase 9 has been suggested to act as apoptosis trigger. Excitingly, it can also prevent epigenetic silencing of BRCA-1 in MCF-7 BC cells. Whether resveratrol acts as an ER agonist or antagonist appears to be dependent, at least in part, on cell type and dosage of resveratrol (
Given the number of clinical studies listed
The assessment of resveratrol induced effects in estrogen-dependent mammary carcinoma tissue versus normal tissues of August Copenhagen Irish (ACI) rats, which develop BC when exposed to 17-β Estradiol, further underlined the epigenetic impact of this compound. First, resveratrol treatment resulted in a lag of tumor development as well as a significant DNMT3b down-regulation in tumors compared to normal mammary tissue. Second, miR-10a and miR-10b showed a marginally significant increase in tumor tissue related to a low dose treatment of 5 mg/kg/day, while high dose resveratrol treatment of 25 mg/kg/day augmented the expression of miR-21, miR-129, miR-204, and miR-489 more than twofold in tumor tissue. A general trend showed inverse proportional miR levels in tumor tissue compared to normal tissue. Furthermore, an inverse correlation of RNA levels between miR-129, 204, 489, and DNMT3b was seen in normal tissue; in tumor tissue, this was only observed for miR-489. DNMT3b is perceived as the prevalent methyltransferase in breast carcinogenesis; hence, the inverse correlation between DNMT3b and miR-129 and 204 needs further examination with respect to its role in tumor development. As an antipode, resveratrol was moreover found to increase miR-21 expression in the ACI rat model, although miR-21 overexpression correlates with advanced BC stages and is linked to aggressiveness along with hormone insensitivity in HER2+ tumors and to various other female malignancies. Due to the fact that the mammary tumors in this study were hormone sensitive and HER2− and miR-21 might have different implications, further analysis will be needed in this model (
In 2002, Anand et al. identified eukaryotic translation elongation factor 1A2 (eEF1A2) as a proto-oncogene in OC. Embodying a key role in protein synthesis by binding aminoacyl-tRNA and transmitting it to the ribosomal A-site, eEF1A2 was found to acquiesce anchorage-independent growth and increase growth of ES-2 ovarian carcinoma cells in nude mice. Recently, a study indicated that miR-663 and miR-744 directly target EEF1A2 expression at mRNA and protein levels. Resveratrol was found to post-transcriptionally down-regulate both mRNA and protein levels by stimulating miR-663 and 744 expression in MCF-7 BC cells implying that it reactivates a miR-mediated silencing mechanism of eEF1A2 (
Along with caloric restriction and blueberry powder, resveratrol has demonstrated to have anti-cancer properties (
In conjunction with curcumin, genistein, and resveratrol, there have been several discoveries on the impact of phytochemicals, such as 3, 3′-diindolylmethane (DIM), sulforaphane, Indole-3-carbinol, and a plethora of other biologically active components on miR signatures in female cancers. To begin with, DIM, a
A major obstacle for HER2+ patients is Herceptin resistance, regardless if gained primarily or secondarily. Circumventing this resistance with the aid of dietary components was addressed in a further study on DIM. Here, a synergism between DIM and Herceptin (Trastuzumab) was ascertained. Combinatorial treatment of SKBR3 cells not only led to the decrease of FoxM1 and phosphorylated AKT, but to a significant increase in miR-200a, miR-200b, and miR-200c as well. Aside from this cell line derived from pleural effusions of breast adenocarcinoma overexpressing Her2/neu, the group employed the TNBC cell line MDA-MB-468. Cotreatment of MDA-MB-468 cells showed cytotoxic effects and a significant up-regulation of miR-200a and miR-200b. Transfection studies in both cell lines revealed that pre-miR-200 in combination with DIM and Herceptin treatment decreased FoxM1 and NFκB p65 expression, indicating that this down-regulation is mediated through miR-200. Hence, important findings toward vanquishing Herceptin resistance as well as providing a new basis for the future treatment of patients with TNBC have been made. Comprehensive investigations on how the synergism of DIM with Herceptin or other drugs such as Paclitaxel works on a molecular basis and applying those findings to cancer therapy will need to be further pursued (
Another phytochemical obtained from cruciferous vegetables is the isothiocyanate sulforaphane, which has been reported to reduce the risk of cancer development. A plethora of studies on its molecular impacts, including epigenetic effects, have been made, and cues that early-life consumption of sulforaphane as well as exposure of the embryo
A very recent finding indicates that Indole-3-carbinol (I3C) is able to induce cell cycle arrest and stimulate miR-34a expression in the BC cell line MCF-7 in a wild-type p53 dependent response. As a result, miR-34a target CDK4 is suppressed. Interestingly, this is one of the first studies aiming at deeper mechanistic insights on the mode of action of phytochemicals and their impact on miR levels in female cancers (
Among the most consumed beverages worldwide is tea, and the catechins occurring in green tea are known to be biologically active. We demonstrated that EGCG, a major polyphenol of green tea, induces apoptosis in Paclitaxel- and Cisplatin-resistant OC cells through modulating cellular signals and enzymes like hTERT. The role of miR epigenetics, however, remains to be fully explored (
Pomegranate contains the polyphenols punicalagin A and B (ellagitannins) and delphinidin 3-glucoside, cyanidin-3-glucoside (anthocyanins), as well as ellagic acid glucoside and free ellagic acid. These polyphenols abolish cancer-promoting characteristics of estrogen and sensitize ERα+, tamoxifen-sensitive and, -resistant cancer cells to tamoxifen treatment. Pomegranate extract induces a decrease of miR-155 followed by a rise in SHIP-1 (Inositol 5‘phosphatase) mRNA and protein expression along with an inhibition of the PI3K dependent AKT phosphorylation. The transcription factors Sps (specificity proteins) are frequently overexpressed in a variety of tumors, and can be inhibited by the zinc finger protein ZBTB10. Pomegranate polyphenols were shown to down-regulate miR-27a, a suppressor of ZBTB10, hence leading to an up-regulation of ZBTB10 and an abolishment of Sp (Figure
Aside from the prominent phytochemicals such as curcumin, genistein, or resveratrol, further remarkable compounds found in nature have been reported to affect miR signatures in female cancers. This section addresses betulinic acid, 1′S-1′-acetoxychavicol acetate, garcinol, glyceollins, matrine, artemisinin, and certain vitamins with respect to miR levels and the resulting effects in female cancer models.
Alongside pomegranate polyphenols, betulinic acid, a pentacyclic triterpenoid rife in barks of trees such as
In addition to the DIM-Herceptin synergism, an interesting observation was made by Phuah et al.
Garcinol, a polyisoprenylated benzophenone derivative found in
Soy plants grown in stress conditions produce a large quantum of the phytoalexins glyceollin I–III.
Present studies on the alkaloid matrine from
The phytochemical artemisinin, a compound found in the sweet wormwood plant, and its derivative artesunate, have been studied as compounds against BC recently. Exhibiting potent anti-malarial activity, artemisinin and its derivative artesunate have a peroxide moiety that can react with iron resulting in the formation of free radicals. Due to the fact that cancer cells hold more intracellular free iron, these compounds act cancer-cell specific (
Although vitamins are not primarily considered phytochemicals, a part of these are essential nutrients with a demonstrable impact on miR signatures in breast and gynecological cancers. One of them is ascorbic acid (vitamin C). Ascorbic acid up-regulates expression of NRF2 as well as NRF2- related genes, superoxide dismutase and NAD(P)H:quinone oxidoreductase, by decreasing miR-93 levels in MCF10A and T47D cells. Furthermore, reduced levels in NRF2 due to an increase of miR-93 were reversed upon vitamin C treatment in an E2-induced ACI rat model. In MCF10A cells, miR-93 suppression promoted a decrease in colony and mammosphere formation as well as apoptosis induction. These findings highlight not only a further mechanism through which diet can influence cancer but also a possible combinatorial approach of cancer treatment in the future (
Vitamin D3 occurs in several forms, such as calcitriol and calcifediol. Both are synthesized by the body itself and exert hormonal function; nevertheless, supplementing vitamin D3 in 30–80 ng/ml doses were determined as beneficial in terms of carcinogenesis. 1, 25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) as a modulator of the immune system, cancer cell proliferation, and apoptosis. Ligand binding to the VDR is followed by heterodimerization with the retinoid X receptor (RXR) and consequently interaction with vitamin D-responsive elements in the regulatory region of according genes. Kasiappan et al. substantiated that in response to calcitriol treatment, not only
Because cholecalciferol may confer toxicity in terms of evoking hypercalcemia, the prohormone calcifediol has gained attention as it is able to protect against cellular stress, such as hypoxia or induction of ROS, a risk factor for developing cancer. In a study performed with non-malignant MCF12F breast epithelial cells, five miRs (miR-26b, miR-182, miR-200c, miR-200b, and let-7b) have been identified to be comprised in the cellular stress response (
ClinicalTrials.gov2 listed 407 studies to date and counting on the effect of diet on female cancers revealing the ubiquitous understanding that nutrition can have a beneficial influence on cancer prevention and treatment. This is supported by the plethora of findings which substantiate that nutraceuticals are important in primary, secondary, and tertiary chemoprevention as well as in combination with chemotherapeutic agents. Reactivation of ERα or enhancing the effect of Cisplatin, Herceptin, and various other chemotherapeutics implies the necessity of a combinatorial therapeutic approach for cancer therapy. Therefore, the all-embracing understanding of the molecular mechanisms induced by these compounds is not only salutary but inevitable: examining miR patterns and their associated phenotypes in response to phytochemical treatment is a central approach.
In fact, little is known on the structure-activity relationship of phytochemicals with miRs in female cancers. Major open questions, such as in which manner phytochemicals can bind to miRs or their genes, as well as mechanistic insights into feed-back loops or pathways leading to the phytochemical-induced miR level alteration, remain. First findings reveal that p53 status may be a key factor for some compounds. In this connection, patients with certain tumor characteristics, such as a p53 negative status, may not benefit from a compound that is only effective in patients with p53 wild-type positive cancers (
As indicated before, a future perspective is the co-administration of chemotherapy with a single or a combination of phytochemicals. Chemotherapy is administered depending on the patients’ tumor characteristics; however, there is a lack of knowledge about which cancer genotype as well as phenotype will benefit from additional phytochemical treatment. Moreover, little is known about the interaction between phytochemical and chemotherapy agents. As emphasized before, DIM and Herceptin; ACA and Cisplatin may be efficient combinations for therapy of female cancers. Sulforaphane has been reported to enhance drug cytotoxicity of various chemotherapeutics in prostate and pancreatic CSC, if this may apply to female cancers and the according CSCs as well will need further investigations (
Yet, when it comes to dealing with miR profiling studies, there are currently limitations in terms of the outcome. Nair et al. showed in their analysis of 43 miR profiling studies that significant interstudy irregularities concerning the amount of cohorts/samples and external validations existed among the studies. This suggests to remit guidelines in order to bring different studies down to a common denominator and to facilitate assessment of varying inter-study results achieved in the future (
Excitingly, there has been a mechanism leading to transcriptional activation known as RNA activation (RNAa) described. Through targeting promoter sequences by double-stranded saRNA (small activating RNA), gene expression was activated. Further investigations on how saRNA or rather miRs can manipulate cell fate as well as screening for endogenous activating RNAs in humans is necessary. Huang et al. demonstrated that in mouse cells an endogenous system exists, activating gene expression through miRs (
In conclusion, phytochemicals exert their anti-inflammatory, anti-oxidant, and anti-cancer effects along with a variety of other functions not only through targeting epigenetic modulators such as HATs, HDACs, and DNMTs but also through targeting miRs, which are feasible for influencing these aforementioned modulators as well as further cellular signaling cascades. Not only phytochemicals such as curcumin, genistein, or resveratrol but vitamin C, D3, and polyunsaturated fatty acid from fish oil have been shown to impact miR patterns in female cancers. Hence, including phytochemicals in treatment is likely to enhance the outcome of diseases such as female cancers at minimum risk. As more data become available, knowledge about miR profiles and their implication converges with medicine and personalized treatment (
Considering the presented aspects and approaches, the knowledge on how nutrition significantly changes or interferes in cross-talk among pathways of miRs is a matter of great prominence, especially for developing new treatments targeted at low treatment-responsive female cancers.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported in part by grants from the NCI (ROI CA178441) and the American Institute for Cancer Research (316184). I acknowledge furthermore the lab members of the Tollefsbol laboratory.
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