Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Magdeburg, 39106, Germany.
Present address: Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
Cell Commun Signal. 2024 Mar 6;22(1):161. doi: 10.1186/s12964-024-01542-9.
Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is especially aggressive and associated with high metastasis. The aetiology of TNBC is heterogeneous and characterised by multiple different mutations that amongst others cause constitutive and dysregulated MAPK and PI3K signalling. Additionally, in more than 50% of TNBC patients, the epidermal growth factor receptor (EGFR) is overexpressed and constitutively active. The multi-site docking protein Grb2-associated binder 1 (Gab1) is a central signalling hub that connects MAPK and PI3K signalling.
Expression and activation of members of the Gab1/PI3K/MAPK signalling network were assessed in cells from different breast cancer subtypes. Influence of short- and long-term inhibition of EGFR, MAPK and PI3K on the activation of the Gab1/PI3K/MAPK signalling network as well as on cell viability, proliferation and migration was determined. Additionally, cellular localisation of Gab1 and Gab1 variants in naive cells and cells treated with the above-mentioned inhibitors was investigated.
We show that, activation of the Gab1/PI3K/MAPK signalling network is heterogeneous between different breast cancer subtypes. Gab1 phosphorylation and plasma membrane recruitment of Gab1 are dysregulated in the EGFR TNBC cell line MDA-MB-468. While the Gab1/MAPK/PI3K signalling network follows canonical Gab1 signalling in naive MDA-MB-468 cells, Gab1 signalling is changed in cells that acquired resistance towards MAPK and PI3K inhibition. In resistant cells, Gab1 is not located at the plasma membrane despite strong activation of PI3K and MAPK. Furthermore, Gab1 tyrosine phosphorylation is uncoupled from plasma membrane recruitment.
Our study indicates that Gab1 signalling changes fundamentally during the acquisition of resistance to pharmacological inhibitors. Given the molecular heterogeneity between breast cancer subtypes, the detailed understanding of dysregulated and aberrant signalling is an absolute necessity in order to develop personalised therapies for patients with TNBC.
乳腺癌是全球女性最常见的癌症。三阴性乳腺癌（TNBC）特别具有侵袭性，并且与高转移率相关。TNBC 的病因具有异质性，其特征是多种不同的突变，这些突变除其他外导致组成型和失调的 MAPK 和 PI3K 信号传导。此外，在超过 50%的 TNBC 患者中，表皮生长因子受体（EGFR）过表达并持续激活。多位点 docking 蛋白 Grb2 相关结合蛋白 1（Gab1）是连接 MAPK 和 PI3K 信号的中央信号枢纽。
评估了不同乳腺癌亚型细胞中 Gab1/PI3K/MAPK 信号网络成员的表达和激活。确定了短期和长期抑制 EGFR、MAPK 和 PI3K 对 Gab1/PI3K/MAPK 信号网络的激活以及对细胞活力、增殖和迁移的影响。此外，还研究了在上述抑制剂处理的幼稚细胞和细胞中 Gab1 和 Gab1 变体的细胞内定位。
我们表明，不同乳腺癌亚型之间 Gab1/PI3K/MAPK 信号网络的激活具有异质性。在 EGFR TNBC 细胞系 MDA-MB-468 中，Gab1/PI3K/MAPK 信号网络的 Gab1 磷酸化和质膜募集失调。虽然在幼稚 MDA-MB-468 细胞中 Gab1/MAPK/PI3K 信号遵循典型的 Gab1 信号，但在获得 MAPK 和 PI3K 抑制耐药性的细胞中 Gab1 信号发生改变。在耐药细胞中，尽管 PI3K 和 MAPK 强烈激活，但 Gab1 不在质膜上。此外，Gab1 酪氨酸磷酸化与质膜募集脱耦。
我们的研究表明，在获得对药理抑制剂的耐药性过程中，Gab1 信号发生了根本性的变化。鉴于乳腺癌亚型之间的分子异质性，为了为 TNBC 患者开发个性化治疗方法，详细了解失调和异常信号是绝对必要的。
