RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer

  1. Yang Liu
  2. Yi Jiang
  3. Peng Qiu
  4. Tie Ma
  5. Yang Bai
  6. Jiawen Bu
  7. Yueting Hu
  8. Ming Jin
  9. Tong Zhu
  10. Xi Gu

  • Curated by eLife

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    eLife assessment

    This study presents a valuable finding on the mechanism to promote distant metastasis in breast cancer. The evidence supporting the claims of the authors is convincing. The work will be of interest to medical biologists working on breast cancer.

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Abstract

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial–mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulate metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and miR-539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

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  1. Version published to 10.1101/2024.03.04.583283v2 on bioRxiv
  2. eLife

    eLife assessment

    This study presents a valuable finding on the mechanism to promote distant metastasis in breast cancer. The evidence supporting the claims of the authors is convincing. The work will be of interest to medical biologists working on breast cancer.

  3. eLife

    Reviewer #1 (Public Review):

    Strengths

    The paper has shown the expression of RGS10 is related to the molecular subtype, distant metastasis, and survival status of breast cancer. The study utilizes bioinformatic analyses, human tissue samples, and in vitro and in vivo experiments which strengthen the data. RGS10 was validated to inhibit EMT through a novel mechanism dependent on LCN2 and miR-539-5p, thereby reducing cancer cell proliferation, colony formation, invasion, and migration. The study elaborated the function of RGS10 in influencing the prognosis and biological behavior which could be considered as a potential drug target in breast cancer.

    Weakness
    The mechanism by which the miR-539-5p/RGS10/LCN2 axis may be related to the prognosis of cancer patients still needs to be elucidated. In addition, the sample size used is relatively limited. Especially, if further exploration of the related pathways and mechanisms of LCN2 can be carried out by using organoid models, as well as the potential of RGS10 as a biomarker for further clinical translation to verify its therapeutic target effect, which will make the data more convincing.

  4. eLife

    Reviewer #2 (Public Review):

    Liu et al., by focusing on the regulation of G protein-signaling 10 (RGS10), reported that RGS10 expression was significantly lower in patients with breast cancer, compared with normal adjacent tissue. Genetic inhibition of RGS10 caused epithelial-mesenchymal transition, and enhanced cell proliferation, migration, and invasion, respectively. These results suggest an inhibitory role of RGS10 in tumor metastasis. Furthermore, bioinformatic analyses determined signaling cascades for RGS10-mediated breast cancer distant metastasis. More importantly, both in vitro and in vivo studies evidenced that alteration of RGS10 expression by modulating its upstream regulator miR-539-5p affects breast cancer metastasis. Altogether, these findings provide insight into the pathogenesis of breast tumors and hence identify potential therapeutic targets in breast cancer.

    The conclusions of this study are mostly well supported by data. However, there is a weakness in the study that needs to be clarified.

    In Figure 2A, although some references supported that SKBR3 and MCF-7 possess poorly aggressive and less invasive abilities, examining only RGS10 expression in those cells, it could not be concluded that 'RGS10 acts as a tumor suppressor in breast cancer'. It would be better to introduce a horizontal comparison of the invasive ability of these 3 types of cells using an invasion assay.

  5. eLife

    Reviewer #3 (Public Review):

    Distant metastasis is the major cause of death in patients with breast cancer. In this manuscript, Liu et al. show that RGS10 deficiency elicits distant metastasis via epithelial-mesenchymal transition in breast cancer. As a prognostic indicator of breast cancer, RGS10 regulates the progress of breast cancer and affects tumor phenotypes such as epithelial-mesenchymal transformation, invasion, and migration. The conclusions of this paper are mostly well supported by data, but some analyses need to be clarified.

    (1) Because diverse biomarkers have been identified for EMT, it is recommended to declare the advantages of using RGS10 as an EMT marker.

    (2) The authors utilized databases to study the upstream regulatory mechanisms of RSG10. It is recommended to clarify why the authors focused on miRNAs rather than other epigenetic modifications.

    (3) The role of miR-539-5p in breast cancer has been described in previous studies. Hence, it is recommended to provide detailed elaboration on how miR-539-5p regulates the expression of RSG10.

    (4) To enhance the clarity and interpretability of the Western blot results, it would be advisable to mark the specific kilodalton (kDa) values of the proteins.

  6. Version published to 10.1101/2024.03.04.583283v1 on bioRxiv
  7. Version published to 10.7554/elife.97327 on eLife
  8. Version published to 10.7554/elife.97327.1 on eLife