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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

PAC down-regulates estrogen receptor alpha and suppresses epithelial-to-mesenchymal transition in breast cancer cells

Authors: Huda A. Al-Howail, Hana A. Hakami, Basem Al-Otaibi, Amer Al-Mazrou, Maha H. Daghestani, Ibrahim Al-Jammaz, Huda H. Al-Khalaf, Abdelilah Aboussekhra

Published in: BMC Cancer | Issue 1/2016

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Abstract

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.
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Metadata
Title
PAC down-regulates estrogen receptor alpha and suppresses epithelial-to-mesenchymal transition in breast cancer cells
Authors
Huda A. Al-Howail
Hana A. Hakami
Basem Al-Otaibi
Amer Al-Mazrou
Maha H. Daghestani
Ibrahim Al-Jammaz
Huda H. Al-Khalaf
Abdelilah Aboussekhra
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2583-8

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