Open Access

HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression

  • Authors:
    • Tomoya Takeda
    • Masanobu Tsubaki
    • Shuji Genno
    • Kenta Tokunaga
    • Remi Tanaka
    • Shozo Nishida
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  • Published online on: July 19, 2023     https://doi.org/10.3892/ijmm.2023.5283
  • Article Number: 80
  • Copyright: © Takeda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple‑negative breast cancer (TNBC), a highly metastatic subtype of breast cancer, and it has the worst prognosis among all subtypes of breast cancer. However, no effective systematic therapy is currently available for TNBC metastasis. Therefore, novel therapies targeting the key molecular mechanisms involved in TNBC metastasis are required. The present study examined whether the expression levels of human epidermal growth factor receptor 3 (HER3) were associated with the metastatic phenotype of TNBC, and evaluated the potential of HER3 as a therapeutic target in vitro and in vivo. A new highly metastatic 4T1 TNBC cell line, termed 4T1‑L8, was established. The protein expression levels in 4T1‑L8 cells were measured using luminex magnetic bead assays and western blot analysis. The HER3 expression levels and distant metastasis‑free survival (DMFS) in TNBC were analyzed using Kaplan‑Meier Plotter. Transwell migration and invasion assays were performed to detect migration and invasion. The anti‑metastatic effects were determined in an experimental mouse model of metastasis. The results revealed that the increased expression of the HER3/Akt/mTOR pathway was associated with a greater level of cell migration, invasion and metastasis of TNBC cells. In addition, it was found that high expression levels of HER3 were associated with a poor DMFS. The inhibition of the HER3/Akt/mammalian target of rapamycin (mTOR) pathway decreased the migration, invasion and metastasis of TNBC cells by decreasing the expression of C‑X‑C chemokine receptor type 4 (CXCR4). Furthermore, treatment of metastatic TNBC cells with everolimus inhibited their migration, invasion and metastasis by decreasing CXCR4 expression. Thus, targeting the HER3/Akt/mTOR pathway opens up a new avenue for the development of therapeutics against TNBC metastasis; in addition, everolimus may prove to be an effective therapeutic agent for the suppression of TNBC metastasis.
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September-2023
Volume 52 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Takeda T, Tsubaki M, Genno S, Tokunaga K, Tanaka R and Nishida S: HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression. Int J Mol Med 52: 80, 2023
APA
Takeda, T., Tsubaki, M., Genno, S., Tokunaga, K., Tanaka, R., & Nishida, S. (2023). HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression. International Journal of Molecular Medicine, 52, 80. https://doi.org/10.3892/ijmm.2023.5283
MLA
Takeda, T., Tsubaki, M., Genno, S., Tokunaga, K., Tanaka, R., Nishida, S."HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression". International Journal of Molecular Medicine 52.3 (2023): 80.
Chicago
Takeda, T., Tsubaki, M., Genno, S., Tokunaga, K., Tanaka, R., Nishida, S."HER3/Akt/mTOR pathway is a key therapeutic target for the reduction of triple‑negative breast cancer metastasis via the inhibition of CXCR4 expression". International Journal of Molecular Medicine 52, no. 3 (2023): 80. https://doi.org/10.3892/ijmm.2023.5283