Cullin7 enhances resistance to trastuzumab therapy in Her2 positive breast cancer via degrading IRS-1 and downregulating IGFBP-3 to activate the PI3K/AKT pathway

• Published in: Cancer letters 2019-11, Vol.464, p.25-36
• Main Authors: Qiu, Ni, He, Yu-fang, Zhang, Si-ming, Zhan, Yong-tao, Han, Guo-dong, Jiang, Ming, He, Wei-xing, Zhou, Jie, Liang, Hong-ling, Ao, Xiang, Xia, Hao-ming, Li, Jia, Yang, Yu-yang, He, Zhi-min, Zou, Zheng-zhi, Li, Hong-sheng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Survival; Cullin Proteins - genetics; Cullin7; Down-Regulation; Drug dosages; Drug resistance; Drug Resistance, Neoplasm; ErbB-2 protein; Female; Flow cytometry; Gene Amplification; Her2-amplified breast cancer; Humans; Immunotherapy; Insulin Receptor Substrate Proteins - chemistry; Insulin Receptor Substrate Proteins - metabolism; Insulin receptor Substrate-1; Insulin resistance; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Kinases; Laboratory animals; Medical prognosis; Metastasis; Mice; Monoclonal antibodies; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteins; Proteolysis; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - genetics; Signal transduction; Statistical analysis; Targeted cancer therapy; TOR protein; Trastuzumab; Wnt protein
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.08.008

Patients with Her2-positive breast cancer exhibit de novo resistance or develop acquired resistance in less than one year after Her2 targeting treatment, but the mechanism is not fully elucidated. Compensatory pathways such as the IGF-1R/IRS-1 pathway, are activated, leading to aberrant enhanced PI3K/Akt/mTOR pathway activity to attenuate the efficacy of trastuzumab. Cullin7 could participate in the degradation of IRS-1 in a mTOR/S6K dependent manner. Whether Cullin7 participates in trastuzumab resistance needs to be further investigated. Here, we reveals that Cullin7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells. Knockdown of Cullin7 reduces degradation of Ser phosphorylation of IRS-1, attenuates activation of the PI3K/AKT pathway, and partly restores trastuzumab sensitivity in trastuzumab-resistant Her2 positive breast cancer cells. IGFBP-3 expression is decreased in trastuzumab-resistant Her2 positive breast cancer cells, which leads to release of the Wnt signaling pathway inhibition and an increase in Cullin7 expression, as mediated by TCF7L2. Overexpression of Cullin7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers. •Cullin 7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells.•Cullin 7 activated PI3K/AKT pathway to induce trastuzumab-resistant.•Cullin7 confers trastuzumab-resistance via degrading IRS-1 to modulate the PI3K/AKT pathway in Her2 positive breast cancer.