Downregulation of RGS10 Promotes Distant Metastasis by Inducing Epithelial-Mesenchymal Transition in Breast Cancer

Core Concepts

Downregulation of RGS10 promotes epithelial-mesenchymal transition, invasion, and metastasis in breast cancer through the miR-539-5p/RGS10/LCN2 axis.

Abstract

The study investigated the role of RGS10, a regulator of G protein signaling, in breast cancer metastasis. Key findings:

RGS10 expression was significantly lower in breast cancer tissues compared to normal breast tissues. Low RGS10 expression predicted worse prognosis in breast cancer patients.

Silencing RGS10 in the SKBR3 breast cancer cell line enhanced epithelial-mesenchymal transition (EMT), migration, and invasion.

The tumor-suppressive effects of RGS10 were mediated through the regulation of lipocalin-2 (LCN2) and miR-539-5p. Overexpression of miR-539-5p downregulated RGS10 and promoted EMT, migration, and invasion in breast cancer cells.

In vivo, RGS10 depletion in SKBR3 cells led to increased tumor growth and upregulation of EMT markers like LCN2, snail, and vimentin.

These results identify RGS10 as a novel tumor suppressor that inhibits breast cancer metastasis by regulating the miR-539-5p/RGS10/LCN2 axis and EMT. RGS10 may serve as a prognostic biomarker and potential therapeutic target in breast cancer.

Stats

RGS10 mRNA levels were significantly lower in breast cancer tissues compared to adjacent normal breast tissues (P=0.003).
Patients with high RGS10 mRNA expression had significantly improved disease-free survival (P=0.0066) and overall survival (P=0.027) compared to those with low RGS10 expression.
Silencing RGS10 in SKBR3 breast cancer cells significantly increased cell proliferation, colony formation, migration, and invasion.

Quotes

"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."

Key Insights Distilled From

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

by Liu,Y., Jian... at www.biorxiv.org 03-06-2024

https://www.biorxiv.org/content/10.1101/2024.03.04.583283v1

Deeper Inquiries

How could the miR-539-5p/RGS10/LCN2 axis be therapeutically targeted to prevent breast cancer metastasis

The miR-539-5p/RGS10/LCN2 axis presents a promising target for therapeutic interventions to prevent breast cancer metastasis. One approach could involve the development of miR-539-5p mimics or RGS10 activators to enhance the expression and activity of RGS10, thereby inhibiting LCN2-mediated EMT. By increasing RGS10 levels or activity, the axis could be modulated to suppress EMT and reduce the invasive and metastatic potential of breast cancer cells. Additionally, targeting LCN2 directly through specific inhibitors or antibodies could disrupt its pro-metastatic effects, further inhibiting the progression of breast cancer.

What other signaling pathways or transcriptional regulators might interact with the RGS10-mediated suppression of EMT in breast cancer

In addition to the miR-539-5p/RGS10/LCN2 axis, several other signaling pathways and transcriptional regulators may interact with RGS10-mediated suppression of EMT in breast cancer. One potential interaction could involve the TGF-β signaling pathway, which is known to play a crucial role in promoting EMT in various cancers, including breast cancer. RGS10 may modulate TGF-β signaling to inhibit EMT and metastasis. Furthermore, transcription factors such as Snail, Slug, ZEB1, and Twist, which are key regulators of EMT, could interact with RGS10 to coordinate the expression of EMT-related genes and maintain the epithelial phenotype in breast cancer cells.

Could RGS10 expression or activity be modulated to enhance the efficacy of existing breast cancer therapies

Modulating RGS10 expression or activity could offer a novel approach to enhance the efficacy of existing breast cancer therapies. For instance, combining RGS10-targeted therapies with standard chemotherapeutic agents could potentially sensitize breast cancer cells to treatment, leading to improved outcomes for patients. By restoring RGS10 levels in aggressive breast cancer cells, the response to chemotherapy or targeted therapies could be enhanced, reducing the risk of metastasis and improving overall survival rates. Additionally, RGS10 modulation could be explored in combination with immunotherapies or hormone therapies to create synergistic effects and overcome treatment resistance in breast cancer.