There is a potential correlation between G-protein-coupled receptor-associated sorting protein 1 (GASP1) and breast tumorigenesis. However, its biological function and underlying molecular mechanism in breast cancer have not been clearly delineated. Here, we demonstrated that GASP1 was highly expressed in breast cancers, and patients harboring altered GASP1 showed a worse prognosis than those with wild-type GASP1. Functional studies showed that GASP1 knockout significantly suppressed malignant properties of breast cancer cells, such as inhibition of cell proliferation, colony formation, migration, invasion and xenograft tumor growth in nude mice as well as induction of G1-phase cell cycle arrest, and vice versa. Mechanistically, GASP1 inhibited proteasomal degradation of insulin-like growth factor 1 receptor (IGF1R) by competitively binding to IGF1R with ubiquitin E3 ligase MDM2, thereby activating its downstream signaling pathways such as NF-κB, PI3K/AKT, and MAPK/ERK pathways given their critical roles in breast tumorigenesis and progression. IGF1, in turn, stimulated GASP1 expression by activating the PI3K/AKT pathway, forming a vicious cycle propelling the malignant progression of breast cancer. Besides, we found that GASP1 knockout obviously improved the response of breast cancer cells to paclitaxel. Collectively, this study demonstrates that GASP1 enhances malignant behaviors of breast cancer cells and decreases their cellular response to paclitaxel by interacting with and stabilizing IGF1R, and suggests that it may serve as a valuable prognostic factor and potential therapeutic target in breast cancer.

G 蛋白偶联受体相关分选蛋白 1 (GASP1) 与乳腺肿瘤发生之间存在潜在相关性。然而，其在乳腺癌中的生物学功能和潜在分子机制尚未明确描述。在这里，我们证明了 GASP1 在乳腺癌中高表达，携带改变的 GASP1 的患者比携带野生型 GASP1 的患者预后更差。功能研究表明，GASP1 敲除显着抑制了乳腺癌细胞的恶性特性，例如抑制细胞增殖、集落形成、迁移、侵袭和裸鼠异种移植肿瘤生长以及诱导 G1 期细胞周期停滞，反之亦然. 从机械上讲，GASP1 通过与泛素 E3 连接酶 MDM2 竞争性结合 IGF1R，抑制胰岛素样生长因子 1 受体 (IGF1R) 的蛋白酶体降解，从而激活其下游信号通路，如 NF-κB、PI3K/AKT 和 MAPK/ERK 通路，因为它们具有关键作用在乳腺肿瘤发生和发展中的作用。IGF1反过来又通过激活PI3K/AKT通路刺激GASP1的表达，形成恶性循环，推动乳腺癌的恶性进展。此外，我们发现GASP1敲除明显改善了乳腺癌细胞对紫杉醇的反应。总的来说，这项研究表明，GASP1 通过与 IGF1R 相互作用并稳定 IGF1R，增强了乳腺癌细胞的恶性行为并降低了它们对紫杉醇的细胞反应，