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Updated: Mar 17, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
PAC down-regulates estrogen receptor alpha and suppresses epithelial-to-mesenchymal transition in breast cancer cells
Huda A Al-Howail1, Hana A Hakami1,2,3, Basem Al-Otaibi4
1Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
Background:
Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features.
Methods:
HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities.
Results:
PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERα(+)) and estrogen receptor alfa negative (ERα(-)) breast cancer cells to PAC, which down-regulated ERα in both cell types. This led to complete disappearance of ERα in ERα(-) cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERα in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERα inhibits PAC-dependent induction of apoptosis, which could be mediated through ERα down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts.
Conclusion:
These results indicate that PAC could be considered as important candidate for future therapeutic options against the devastating TNBC subtype.
Insights
PAC, a curcumin analog, shows potent anti-cancer effects, particularly against triple-negative breast cancer (TNBC). It is more stable than curcumin and effectively inhibits cancer cell proliferation and metastasis.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited therapeutic options and poor prognosis.
- Novel therapeutic agents are urgently required to address treatment resistance and disease progression in TNBC.
- PAC, a novel curcumin analogue, has demonstrated promising anti-cancer properties.
Purpose of the Study:
- To evaluate the stability and anti-cancer efficacy of PAC compared to curcumin.
- To investigate the molecular mechanisms underlying PAC's action in various breast cancer subtypes.
- To assess PAC's potential as a therapeutic candidate for TNBC.
Main Methods:
- High-performance liquid chromatography (HPLC) for stability assessment in biological media.
- Flow cytometry with propidium iodide/annexin V for apoptosis analysis.
- Immunoblotting to determine effects on oncogenic proteins and pathways.
- xCELLigence RTCA technology to assess proliferation, migration, and invasion.
- In vivo studies using tumor xenografts.
Main Results:
- PAC exhibits superior stability in PBS and blood compared to curcumin.
- PAC demonstrates differential sensitivity in ERα(+) and ERα(-) breast cancer cells, down-regulating ERα and enhancing apoptosis in ERα(+) cells.
- PAC effectively inhibits breast cancer cell proliferation, suppresses epithelial-to-mesenchymal transition (EMT), and reduces IL-6 and MCP-1 secretion.
- Anti-tumor effects of PAC were confirmed in vivo in tumor xenograft models.
- PAC demonstrated higher efficacy against the TNBC subtype.
Conclusions:
- PAC is a stable curcumin analogue with significant anti-cancer activity, particularly against TNBC.
- PAC's ability to down-regulate ERα and inhibit proliferation and EMT makes it a promising candidate for TNBC therapy.
- Further investigation of PAC as a therapeutic option for TNBC is warranted.
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