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The inhibition of the breast cancer by PPARγ agonist pioglitazone through JAK2/STAT3 pathway
X X Jiao1, S Y Lin2, S X Lian3
1Baoshan branch, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Abstract:
Breast cancer, especially triple-negative breast cancer, is one of the deadliest cancers in women. To date, there is a lack of a good therapeutic regimen for it. PPARγ has been reported to be a tumor suppressor and could be activated by many agonists involved in cancer inhibition. Therefore, the expression of PPARγ in breast cancer was analyzed by online software UALCAN whose data were from the TCGA database. The results revealed that the PPARγ expression was reduced in breast cancer tissues. Furthermore, the methylation in the PPARγ promoter was also assayed and the results indicated that the methylation level in the PPARγ promoter in breast cancer tissue was higher than that in normal tissue. In order to verify the methylation in promoter involved in the regulation of gene PPARγ expression, the 5'-Aza and fluorescence assays were performed and the results proved that methylation in promoter participated in gene PPARγ expression regulation. Pioglitazone, a PPARγ agonist, still was not investigated in breast cancer. Therefore, the effects of pioglitazone on breast cancer cells were tested by cell viability, scratch and transwell assays, and results indicated that the pioglitazone has the inhibition effect on the proliferation and migration of breast cancer cells by PPARγ which was correlated with the JAK2/STAT3 pathway. In order to further confirm the inhibition effect of pioglitazone on breast cancer in vivo, the nude mice model was administrated by gavage with pioglitazone. And the results indicated that pioglitazone could inhibit the growth of breast cancer in the PPARγ overexpression group in vivo. In summary, the expression of gene PPARγ was decreased in breast cancer tissues, which was correlated with its methylation in the promoter region. Moreover, pioglitazone could exert its inhibition on breast cancer proliferation and migration by the JAK2/STAT3 pathway.
Insights
Reduced PPARγ expression and increased promoter methylation are linked to breast cancer. The PPARγ agonist pioglitazone inhibited cancer cell proliferation and migration, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer remains a significant health challenge with limited therapeutic options.
- Peroxisome proliferator-activated receptor gamma (PPARγ) functions as a tumor suppressor, with agonists showing potential in cancer inhibition.
- The role of PPARγ and its agonists in breast cancer therapy requires further investigation.
Purpose of the Study:
- To investigate the expression and regulation of PPARγ in breast cancer.
- To evaluate the therapeutic potential of the PPARγ agonist pioglitazone in breast cancer models.
- To elucidate the molecular pathways involved in pioglitazone's anti-cancer effects.
Main Methods:
- Bioinformatic analysis of PPARγ expression using TCGA data (UALCAN).
- Assay of PPARγ promoter methylation and gene expression regulation studies (5'-Aza, fluorescence assays).
- In vitro assays (cell viability, scratch, transwell) and in vivo studies in a nude mice model to assess pioglitazone's effects.
Main Results:
- PPARγ expression was significantly reduced in breast cancer tissues compared to normal tissues.
- Increased methylation in the PPARγ promoter region correlated with decreased gene expression.
- Pioglitazone demonstrated significant inhibition of breast cancer cell proliferation and migration in vitro and tumor growth in vivo, mediated by PPARγ and the JAK2/STAT3 pathway.
Conclusions:
- Decreased PPARγ expression in breast cancer is associated with promoter hypermethylation.
- Pioglitazone exhibits anti-cancer properties in breast cancer by targeting the PPARγ pathway and inhibiting the JAK2/STAT3 signaling cascade.
- Pioglitazone represents a promising therapeutic agent for breast cancer treatment.
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