The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Search Strategy and Data Extraction
3. Peroxisome Proliferator-Activated Receptor γ: Structure, Distribution, and Mechanism of Action
3.1. Genomic Organization and Tissue Distribution of PPARγ
3.2. PPARγ Domain Structure
3.3. The Mechanism of Action of PPARγ
4. PPARγ Agonists
4.1. Natural PPARγ Ligands
4.2. Synthetic PPARγ Ligands
5. The Role of the PPARγ Ligands in Breast Cancer
5.1. In Vitro Studies
5.1.1. Regulation of Cell Growth and Cell Cycle
5.1.2. Regulation of Cell Death
Apoptosis
Autophagy
5.1.3. Regulation of Motility and Invasion
5.1.4. Cross-Talk of PPARγ with Other Signal Transduction Pathways
5.2. In Vivo Studies
5.3. Clinical Studies
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Class | Common Name | IUPAC NAME | Chemical Structure | References |
---|---|---|---|---|
ω-3 PUFAs 1 | Eicosapentaenoic acid (EPA) 20:5(ω-3) | (5Z,8Z,11Z,14Z,17)-Eicosa-5,8,11,14,17-pentaenoic acid | [64,65] | |
Docosahexaenoic acid (DHA) 22:6(ω-3) | (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid | [57,66] | ||
ω-3 PUFA conjugates | Eicosapentaenoyl ethanolamine (EPEA) | (5Z,8Z,11Z,14Z,17)-N-(2-Hydroxyethyl)-eicosa-5,8,11,14,17-pentaenamide | [21] | |
Docosahexaenoyl ethanolamine (DHEA) | (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-Hydroxyethyl)-docosa-4,7,10,13,16,19-hexaenamide | [21] | ||
Eicosapentaenoyl dopamine (EPADA) | (5Z,8Z,11Z,14Z,17)-N-(3,4-Dihydroxyphenethyl)eicosa-5,8,11,14,17-pentaenamide | [67] | ||
Docosahexaenoyl dopamine (DHADA) | (4Z,7Z,10Z,13Z,16Z,19Z)-N-(3,4-Dihydroxyphenethyl)docosa-4,7,10,13,16,19-hexaenamide | [67] | ||
Docosahexaenoyl serotonin (DHA-5-HT) | (4Z,7Z,10Z,13Z,16Z,19Z)-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-docosa-4,7,10,13,16,19-hexaenamide | [30] | ||
ω-6 PUFAs | Linoleic acid (LA) 18:2(ω-6) | (9Z,12Z)-Octadeca-9,12-dienoic acid | [68] | |
9-Hydroxyoctadecadienoic acid(9-HODE) | (9S,10E,12E)-9-Hydroxyoctadeca-10,12-dienoic acid | [69,70] | ||
13-Hydroxyoctadecadienoic acid (13-HODE) | (9Z,11E,13S)-13-Hydroxyoctadeca-9,11-dienoic acid | [69,70] | ||
15-Deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) | (Z)-7-((S,E)-5-((E)-oct-2-en-1-ylidene)-4-oxocyclopent-2-en-1-yl)hept-5-enoic acid | [71] | ||
Conjugated linoleic acid (CLA) | (9Z,11E)-CLA | (9Z,11E)-Octadeca-9,11-dienoic acid | [72] | |
(9E,11E)-CLA | (9E,11E)-Octadeca-9,11-dienoic acid | [72] | ||
(9Z,11Z)-CLA | (9Z,11Z)-Octadeca-9,11-dienoic acid | [72] | ||
(10E,12E)-CLA | (10E,12E)-Octadeca-9,11-dienoic acid | [72] | ||
Nitrated fatty acids | Nitrolinolenic acid | (9Z,12Z)-2-Nitrooctadeca-9,12-dienoic acid | [60] | |
10-Nitrooleic acid | (9Z)-10-Nitrooctadec-9-enoic acid | [61] | ||
Bioactive compounds | Genistein | 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one | [73] | |
Quercetin | 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one | [74] | ||
Luteolin | 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one | [75] |
Class | Common Name | IUPAC Name | Chemical Structure | References |
---|---|---|---|---|
TDZs 1 | Troglitazone | 5-[[4-[(6-Hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione | [88] | |
Ciglitazone | 5-{4-[(1-Methylcyclohexyl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione | [89] | ||
Pioglitazone | 5-[[4-[2-(5-Ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione | [90] | ||
Rosiglitazone | 5-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione | [91] | ||
Edaglitazone | 5-[[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl]methyl]-1,3-thiazolidine-2,4-dione | [78] | ||
Efatutazone | 5-[(4-{[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-1,3-benzodiazol-2-yl]methoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione | [80] | ||
Rivoglitazone | 5-({4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-Yl)methoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione | [79] | ||
SPPARMs 2 | GW0072 | 3-(4-(4-Carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine | [92] | |
Fmoc-l-leucine | 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid | [93] | ||
Balaglitazone | 5-(4-((3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)benzyl)thiazolidine-2,4-dione | [94] | ||
Netoglitazone | 5-[[6-[(2-Fluorophenyl)methoxy]naphthalen-2-yl]methyl]-1,3-thiazolidine-2,4-dione | [95] | ||
NSAIDs 3 | Sulindac sulfide | 5-Fluoro-2-methyl-1-[p-(methylthio)benzylidene]indene-3-acetic acid | [87] | |
Diclofenac | 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid | [87] | ||
Indomethacin | 2-[1-(4-Chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid | [68,84,87] | ||
Ibuprofen | 2-(4-Isobutylphenyl)propanoic acid | [87] |
NCT | Intervention/Treatment | Phase | Eligibility Criteria, Primary Outcome and Purpose | References |
---|---|---|---|---|
NCT01282580 | -Lovaza -ω-3 fatty acid capsules -Dietary fish (canned salmon, albacore) | I | Eligibility criteria: female (≥18 years) having increased risk for breast cancer based on family and personal history with a normal mammogram in the past 12 years and >1 years from pregnancy, lactation, or chemotherapy. Primary outcome: fatty acid profiles of breast adipose tissue. Purpose: to determine the effects of increased fish consumption on serum and breast fat tissue fatty acids and to assess adherence and tolerability of increased dietary intake of fish relative to an ω-3 fatty acid supplement. | [141] |
NCT02150525 | -ω-3 fatty acids —Placebo | II | Eligibility criteria: postmenopausal women (45–65 years) with a history of breast cancer after 12 months from surgery and 3 months from completion of chemotherapy. Subjects must present at least one symptom of atrophic vaginitis. Primary outcome: improvement of vaginitis’ symptoms by oral ω-3 fatty acids. Purpose: to study the effectiveness of ω-3 fatty acid on atrophic vaginitis in postmenopausal breast cancer patients. | NA |
NCT02101970 | -Weight Loss + ω-3 fatty acids -Weight Loss + Placebo | NA | Eligibility criteria: female having evidence of hyperplasia with Masood score of 13 or higher, 500 or more epithelial cells on cytology slide of screening random periareolar fine-needle aspiration, and reasonable hematopoietic, kidney, and liver function. Primary outcome: dropout rate. Purpose: to determine if high dose supplementation with the ω-3 fatty acids EPA and DHA, when added to a weight loss program, is well tolerated and if there is an increase in the favorable change in blood and tissue breast cancer risk factors when compared to weight loss alone. | NA |
NCT02816125 | -Diet supplemented with EPA + DHA -Dietary fat at less than 20% energy + EPA + DHA | III | Eligibility criteria: menstruating and premenopausal women (≥18 years). Primary outcome: fatty acid incorporation into red blood cells and in cell material from nipple aspirate fluid. Purpose: to examine the effect of the combined treatment with EPA and DHA on breast cancer risk factors in healthy premenopausal women. | [142] |
NCT00723398 | -Raloxifene -Lovaza -Lovaza + Raloxifene | NA | Eligibility criteria: no smoker postmenopausal women (35–70 years) without hormone-replaced therapy for at least 6 months. Primary outcome: absolute breast density. Purpose: to evaluate the effects of Raloxifene alone or in combination with omega-3 fatty acids on breast cancer development markers in postmenopausal women. | [143] |
NCT01823991 | -Lovaza -VitaBlue -Placebo | Early I | Eligibility criteria: women (40–70 years) having stage II-IIIA of breast cancer after completion of adjuvant treatment with chemo- and/or radiotherapy in the past 6 months. Primary outcome: cognitive function scores with intervention. Purpose: to evaluate the safety of nutritional intervention with n-3 fatty acids and blueberry anthocyanins on cognitive performance. | NA |
NCT01869764 | -ω-3 fatty acids -Placebo | II | Eligibility criteria: newly diagnosed women (≥18 years) having in situ carcinoma and stage I to III of breast cancer that will receive breast surgery at least after 7 days from the day of enrollment. Tumor size of at least 1 cm. Primary outcome: ω-3 fatty acid levels in breast tissues in plasma and in erythrocytes before and after surgery. Purpose: to study ω-3 fatty acid effects in patients with breast cancer. | NA |
NCT02352779 | -Low doses of ω-3 fatty acid -High dose of ω-3 fatty acid -Placebo | NA | Eligibility criteria: women having a confirmed diagnosis of breast cancer and undergone some type or combination of standard adjuvant treatment. Patients must have cancer-related fatigue. Primary outcome: mean change and standard deviation in cancer-related fatigue. Purpose: to study ω-3 fatty acid in reducing cancer-related fatigue. | [144] |
NCT01385137 | -ω-3-fatty acids -Placebo | III | Eligibility criteria: postmenopausal women with estrogen-receptor positive and/or progesterone-receptor positive invasive breast adenocarcinoma (I-IIIA stage) currently taking a third-generation aromatase inhibitor; patients must be subjected to modified radical mastectomy or breast-sparing surgery. Primary outcome: Brief Pain Inventory (BPI) Worst Pain/Stiffness Score. Purpose: to study ω-3 fatty acid effects in muscle, bone pain, and stiffness in breast cancer patients receiving hormone therapy. | [145] |
NCT01252277 | -Lovaza | II | Eligibility criteria: premenopausal female (18–54 years) having a breast cancer risk evaluated on the basis of several criteria. Primary outcome: proportion of subjects that complete an intervention. Purpose: to evaluate the effects of Lovaza on breast cancer biomarkers in premenopausal patients. | [146] |
NCT01252290 | -Lovaza | II | Eligibility criteria: postmenopausal women (25–69 years) having a breast cancer risk evaluated on the basis of several criteria. Primary outcome: proportion of subjects that complete the intervention. Purpose: to evaluate the effects of Lovaza on breast cancer biomarkers in postmenopausal patients. | [147] |
NCT00627276 | -ω-3 fatty acids-Placebo | NA | Eligibility criteria: breast cancer patients having confirmed diagnosis of ductal carcinoma in situ and/or atypical ductal hyperplasia. Primary outcome: genetic evaluation of markers for breast cancer risk and progression, fatty acids profile, occurrence of ductal carcinoma in situ and/or atypical ductal hyperplasia or invasive cancer in tissue samples. Purpose: to study the effects of ω-3 fatty acids in patients with ductal carcinoma in situ and/or atypical ductal hyperplasia. | NA |
NCT01824498 | -Low-fat diet -Low fat with high ω -3 diet-High-fat diet | NA | Eligibility criteria: postmenopausal women (45–70 years) having BMI between 19 and 29. Consumption of a “typical” American diet. Primary outcome: plasma sex hormone levels, Estradiol. Purpose: to determine whether diets designed to increase plasma ω-3 concentrations will favorably affect sex hormone distribution in women in a direction associated with reduced risk of sex hormone-mediated cancer development. | [148,149,150,151] |
NCT02062255 | -Aspirin -ω-3 EPA and DHA -Aspirin + ω-3 EPA and DHA | Early phase I | Eligibility criteria: postmenopausal women (≥18 years). Primary outcome: prostaglandin E2, aromatase, pro-inflammatory cytokines, steroids, and lipids. Purpose: to study the impact of COX2 on sera biomarkers from obese subjects. | NA |
NCT01821833 | -ω-3 fatty acids + paclitaxel -Placebo + paclitaxel | NA | Eligibility criteria women (≥18 years) with breast cancer or ovarian cancer who will receive paclitaxel treatment at least for 2 months. Primary outcome: mean severity of pain. Purpose: to study the effects of ω-3 fatty acids on pain of cancer patients. | NA |
NCT01127867 | -DHA | NA | Eligibility criteria: postmenopausal women (40–70 years) having low serum estradiol level (<40 ng/mL) and BMI 35–50. Primary outcome: evaluation of monocyte aggregations and macrophage markers in fat biopsies. Purpose: to study the effects of DHA in decreasing inflammation in fat tissue and reducing breast cancer risk. | [152] |
NCT01902745 | -Fatigue-reduction diet (typical caloric intake and replacement of some calories with the following foods: whole grains, vegetables, fruit, fatty fish, and nuts and/or seeds) | NA | Eligibility criteria: breast cancer patients (≥18 years) having completed the cancer-related treatments and showing persistent, moderate, or severe fatigue despite standard treatment. Primary outcome: fatigue in breast cancer survivors. Purpose: to expand the data on fatigue-reduction diet in breast cancer survivors | [153] |
NCT00933309 | -Exemestane -Exemestane + Avandamet (rosiglitazone and metformin) | I | Eligibility criteria: postmenopausal women with BMI ≥ 25 kg/m2 having estrogen receptor positive and/or progesterone receptor positive breast cancer along with clinical evidence of metastasis. Primary outcome: Dose-limiting toxicity (DLT). Purpose: to define the highest tolerable dose of Avandamet in combination with exemestane in postmenopausal obese breast cancer patients. | [154] |
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Share and Cite
Augimeri, G.; Giordano, C.; Gelsomino, L.; Plastina, P.; Barone, I.; Catalano, S.; Andò, S.; Bonofiglio, D. The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies. Cancers 2020, 12, 2623. https://doi.org/10.3390/cancers12092623
Augimeri G, Giordano C, Gelsomino L, Plastina P, Barone I, Catalano S, Andò S, Bonofiglio D. The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies. Cancers. 2020; 12(9):2623. https://doi.org/10.3390/cancers12092623
Chicago/Turabian StyleAugimeri, Giuseppina, Cinzia Giordano, Luca Gelsomino, Pierluigi Plastina, Ines Barone, Stefania Catalano, Sebastiano Andò, and Daniela Bonofiglio. 2020. "The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies" Cancers 12, no. 9: 2623. https://doi.org/10.3390/cancers12092623