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Raloxifene potentiates the effect of gefitinib in triple-negative breast cancer cell lines

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Abstract

Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins, including epidermal growth factor receptor (EGFR), have been associated with TNBCs and are considered potential therapeutic targets. However, EGFR inhibitors alone failed to demonstrate a cutting-edge advantage for treating TNBCs over conventional chemotherapies. Studies have shown that selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene also affect TNBC cell viability. The combination of gefitinib and raloxifene was assessed against TNBC cell lines in vitro. Two TNBC cell lines, MDA-MB-231 and MDA-MB-468, were used to investigate the combination of gefitinib and raloxifene on cell viability, DNA synthesis, and apoptosis. The combination was assessed on intracellular signaling pathways, colony formation, migration, and angiogenesis. In the present study, raloxifene, in combination with gefitinib, decreased cell viability. The combination potentiates apoptosis and affects the expression and phosphorylation pattern of proteins involved in cell proliferation, such as NFκB, β-catenin, and EGFR. Furthermore, evidence of apoptosis activation was also observed, along with a decreased cell migration and tumorigenicity of TNBC cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. These results suggested the potential of the combination of raloxifene and gefitinib for the prevention of TNBC growth and the appearance of metastatic events. Our findings provide the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the Emerging Researcher First Grants from the Health Research Council of New Zealand under Grant 11–695. Part of the data presented in this manuscript were shown on a poster presentation at AACR meeting (Cancer Res (2012) 72 (8_Supplement): 4669).

Funding

Funding was provided by Health Research Council of New Zealand,11-695, Taurin

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Authors and Affiliations

  1. Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Building 293, Road 2904 Block 329, Manama, 007, Kingdom of Bahrain

    Sebastien Taurin

  2. Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand

    Rhonda J. Rosengren

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  1. Sebastien Taurin
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Correspondence to Sebastien Taurin.

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Taurin, S., Rosengren, R.J. Raloxifene potentiates the effect of gefitinib in triple-negative breast cancer cell lines. Med Oncol 40, 45 (2023). https://doi.org/10.1007/s12032-022-01909-3

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