GNA13 suppresses proliferation of ER+ breast cancer cells via ERα dependent upregulation of the MYC oncogene

Sep 21, 2026

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GNA13 (Gα13), a downstream G-protein alpha subunit of GPCR signaling, has roles in development and cancer progression, but its subtype-specific function in breast cancer is not fully understood. Low GNA13 expression predicts poorer survival and suppresses ER+ breast cancer cell proliferation. Loss of GNA13 enhances soft-agar colony formation and promotes tumor growth in an orthotopic xenograft model. Mechanistically, GNA13 loss upregulates MYC signaling pathways; MYC knockdown reverses the proliferative effects, and ERα-dependent regulation links GNA13 to MYC at both RNA and protein levels.

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CategoryHealthcare

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Abstract

Introduction

Subramanyan et al. Breast Cancer Research (2024) 26:113 Breast Cancer Research [https://doi.org/10.1186/s13058-024-01866-x](https://doi.org/10.1186/s13058-024-01866-x) RESEARCH Open Access GNA13 suppresses proliferation of ER+ breast cancer cells via ERα dependent upregulation of the MYC oncogene LalithaVaishnavi Subramanyan1, Suhail Ahmed Kabeer Rasheed1, Lijin Wang2, Sujoy Ghosh2,3, Michelle Shi Ning Ong4, Manikandan Lakshmanan4, Mei Wang1,5* and Patrick J. Casey 1,6* Abstract GNA13 (Gα13) is one of two alpha subunit members of the G12/13 family of heterotrimeric G-proteins which mediate signaling downstream of GPCRs. It is known to be essential for embryonic development and vasculogenesis and has been increasingly shown to be involved in mediating several steps of cancer progression. Recent studies found that Gα13 can function as an oncogene and contributes to progression and metastasis of multiple tumor types, including ovarian, head and neck and prostate cancers. In most cases, Gα12 and Gα13, as closely related α-subunits in the subfamily, have similar cellular roles. However, in recent years their differences in signaling and function have started to emerge. We previously identified that Gα13 drives invasion of Triple Negative Breast Cancer (TNBC) cells in vitro. As a highly heterogenous disease with various well-defined molecular subtypes (ER+ /Her2−, ER+ /Her2+, Her2+, TNBC) and subtype associated outcomes, the function(s) of Gα13 beyond TNBC should be explored. Here, wereport the finding that low expression of GNA13 is predictive of poorer survival in breast cancer, which challenges the conventional idea of Gα12/13 being universal oncogenes in solid tumors. Consistently, we found that Gα13 suppresses the proliferation in multiple ER+ breast cancer cell lines (MCF-7, ZR-75-1 and T47D) . Loss of GNA13 expression drives cell proliferation, soft-agar colony formation and in vivo tumor formation in an orthotopic xenograft model. To evaluate the mechanism of Gα13 action, we performed RNA-sequencing analysis on these cell lines and found that loss of GNA13 results in the upregulation of MYC signaling pathways in ER+ breast cancer cells. Simultaneous silencing of MYC reversed the proliferative effect from the loss of GNA13, validating the role of MYC in Gα13 regulation of proliferation. Further, we found Gα13 regulates the expression of MYC, at both the transcript and protein level in an ERα dependent manner. Taken together, our study provides the first evidence for a tumor suppressive role for Gα13 in breast cancer cells and demonstrates for the first time the direct involvement of Gα13 in ER-dependent regulation of MYC signaling. With a few exceptions, elevated Gα13 levels are generally considered to be oncogenic, similar to Gα12 . This study demonstrates an unexpected tumor suppressive role for Gα13 in ER+ breast cancer via regulation of MYC, suggesting that Gα13 can have subtype-dependent tumor suppressive roles in breast cancer. *Correspondence: Mei Wang [mei.wang@duke-nus.edu.sg](mei.wang@duke-nus.edu.sg)[ ](mei.wang@duke-nus.edu.sg)Patrick J. Casey [patrick.casey@duke.edu](patrick.casey@duke.edu) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain per

FAQs

What does the study report about GNA13 expression and breast cancer outcomes?

Low GNA13 expression predicts poorer survival in breast cancer. The findings indicate a tumor-suppressive role for GNA13 in ER+ disease.

How does GNA13 affect proliferation of ER+ breast cancer cells?

GNA13 suppresses proliferation across multiple ER+ cell lines. When GNA13 expression is lost, cell proliferation and colony formation increase.

What mechanism links GNA13 to tumor suppression in ER+ breast cancer?

Loss of GNA13 upregulates MYC signaling pathways. Silencing MYC reverses the proliferative effects, and GNA13 regulates MYC expression in an ERα-dependent manner at RNA and protein levels.

Sep 21, 2026

Upload by Noah