The prognostic implications and tumor-suppressive functions of CYR61 in estrogen receptor-positive breast cancer

Front Immunol. 2024 Jan 8:14:1308807. doi: 10.3389/fimmu.2023.1308807. eCollection 2023.

Abstract

Due to the therapeutic resistance of endocrine therapy and the limited efficacy of immune checkpoint inhibitors in estrogen receptor (ER)-positive breast cancer (BRCA), there is an urgent need to develop novel prognostic markers and understand the regulation of the tumor immune microenvironment (TIME). As a matricellular protein, CYR61 has been shown to either promote or suppress cancer progression depending on cancer types. However, how CYR61 functions in ER-positive BRCA remains elusive. In this study, we comprehensively analyzed the expression of CYR61 in BRCA based on the TCGA and METABRIC databases. Our findings showed that the expression of CYR61 is downregulated in different subtypes of BRCA, which is associated with elevated promoter methylation levels and predicts bad clinical outcomes. By comparing the high or low CYR61 expression groups of ER-positive BRCA patients, we found that CYR61 is intimately linked to the expression of genes involved in tumor-suppressive pathways, such as the TGF-β and TNF signaling pathways, and genes related to cytokine-receptor interaction that may regulate cancer immunity. Moreover, reduced CYR61 expression is associated with an altered TIME that favors cancer progression. Finally, experimental analyses ascertained that CYR61 is downregulated in clinical BRCA tissues compared to matched normal breast tissues. Furthermore, CYR61 is able to impede the proliferation and colony formation of ER-positive BRCA cells. In summary, our study reveals that CYR61 could serve as a novel prognostic marker for ER-positive BRCA, and function as an inhibitor of cancer progression by both acting on cancer cells and remodeling the TIME.

Keywords: Cyr61; ER-positive breast cancer; cancer cell proliferation; immune cell infiltration; tumor immune microenvironment (TIME).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast
  • Breast Neoplasms* / genetics
  • Cytokines
  • Female
  • Humans
  • Prognosis
  • Receptors, Estrogen
  • Tumor Microenvironment / genetics

Substances

  • Cytokines
  • Receptors, Estrogen

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Natural Science Foundation of China (NSFC, 32370765 and 32060162), the Natural Science Foundation of Jiangxi Province of China (20224ACB206032, 20224BAB206002 and 20202BAB206046) and the Jiangxi Province Graduate Innovation Fund (YC2018-B017).