GNA13 (Gα13) 是异源三聚体 G 蛋白 G12/13 家族的两个 α 亚基成员之一，介导 GPCR 下游信号传导。众所周知，它对于胚胎发育和血管发生至关重要，并且越来越多的证据表明它参与介导癌症进展的多个步骤。最近的研究发现，Gα13 可以作为癌基因发挥作用，并有助于多种肿瘤类型的进展和转移，包括卵巢癌、头颈癌和前列腺癌。在大多数情况下，Gα12 和 Gα13 作为该亚家族中密切相关的 α 亚基，具有相似的细胞作用。然而，近年来，它们在信号传导和功能上的差异开始显现。我们之前发现 Gα13 在体外驱动三阴性乳腺癌 (TNBC) 细胞的侵袭。作为一种高度异质性的疾病，具有各种明确的分子亚型（ER /Her2-、ER /Her2、Her2、TNBC）和亚型相关结果，应探索 Gα13 在 TNBC 之外的功能。在这里，我们报告了 GNA13 低表达预示着乳腺癌生存率较差的发现，这挑战了 Gα12/13 是实体瘤中普遍癌基因的传统观点。我们一致发现 Gα13 抑制多种 ER 乳腺癌细胞系（MCF-7、ZR-75-1 和 T47D）的增殖。在原位异种移植模型中，GNA13 表达缺失会驱动细胞增殖、软琼脂集落形成和体内肿瘤形成。为了评估 Gα13 的作用机制，我们对这些细胞系进行了 RNA 测序分析，发现 GNA13 的缺失会导致 ER  乳腺癌细胞中 MYC 信号通路的上调。同时沉默 MYC 逆转了 GNA13 缺失造成的增殖效应，验证了 MYC 在 Gα13 增殖调节中的作用。此外，我们发现 Gα13 在转录物和蛋白质水平上以 ERα 依赖性方式调节 MYC 的表达。总之，我们的研究为 Gα13 在乳腺癌细胞中的肿瘤抑制作用提供了第一个证据，并首次证明 Gα13 直接参与 ER 依赖性 MYC 信号传导的调节。除少数例外，Gα13 水平升高通常被认为具有致癌性，与 Gα12 类似。这项研究证明了 Gα13 通过调节 MYC 在 ER 乳腺癌中发挥了意想不到的肿瘤抑制作用，表明 Gα13 在乳腺癌中具有亚型依赖性肿瘤抑制作用。© 2024。作者。

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, we report 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.© 2024. The Author(s).