Guan Yinan, Sun Yulu, Liu Zheying, Zhang Yin, Cao Meng, Wang Wei, Tao Jinqiu, Yao Yongzhong
Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University Nanjing 210008, Jiangsu, China.
Department of Clinical Medicine, Southeast Univeristy School Nanjing 210008, Jiangsu, China.
Am J Cancer Res. 2023 Aug 15;13(8):3500-3516. eCollection 2023.
Insulinoma-associated protein-1 (INSM1), which is highly expressed in various neuroendocrine tumors, functions as a zinc finger transcription factor capable of regulating the biological behavior of tumor cells. However, its specific role in breast cancer remains unclear. This study aims to investigate the role and mechanism of INSM1 in breast cancer. A total of 158 cohorts were recruited to examine the expression of INSM1 in breast cancer tissues and their corresponding adjacent normal tissues using immunohistochemistry. Follow-up data, along with clinical and pathological information, were collected to analyze the correlation between INSM1 expression and survival outcomes in breast cancer patients. Additionally, we investigated the impact of INSM1 on breast cancer cell proliferation, migration, and aggregation. To further explore the regulatory effect of INSM1 knockdown on breast cancer tumor growth, we utilized a xenograft mouse model. The results revealed that INSM1 was significantly overexpressed in breast cancer patients and correlated with prognosis. Knockdown of INSM1 notably impaired the malignant biological effects of breast cancer cells and inhibited the growth of xenograft tumors in nude mice. Importantly, our data also suggests an interaction between INSM1 and S-phase kinase-associated protein 2 (SKP2), which in turn regulates C-MYC, thereby affecting the p-ERK pathway. Our study provides the first evidence demonstrating the contribution of INSM1 to tumor formation and growth in breast cancer. Furthermore, we found that INSM1 positively regulates C-MYC and the p-ERK pathway by interacting with SKP2 during breast cancer development. Collectively, these findings highlight INSM1 as a promising target for breast cancer treatment.
胰岛素瘤相关蛋白-1（INSM1）在多种神经内分泌肿瘤中高表达，作为一种锌指转录因子，能够调节肿瘤细胞的生物学行为。然而，其在乳腺癌中的具体作用仍不清楚。本研究旨在探讨INSM1在乳腺癌中的作用及机制。共招募了158个队列，采用免疫组织化学方法检测乳腺癌组织及其相应癌旁正常组织中INSM1的表达。收集随访数据以及临床和病理信息，分析INSM1表达与乳腺癌患者生存结局之间的相关性。此外，我们研究了INSM1对乳腺癌细胞增殖、迁移和聚集的影响。为了进一步探究敲低INSM1对乳腺癌肿瘤生长的调节作用，我们使用了异种移植小鼠模型。结果显示，INSM1在乳腺癌患者中显著过表达且与预后相关。敲低INSM1显著损害了乳腺癌细胞的恶性生物学效应，并抑制了裸鼠异种移植肿瘤的生长。重要的是，我们的数据还表明INSM1与S期激酶相关蛋白2（SKP2）之间存在相互作用，进而调节C-MYC，从而影响p-ERK通路。我们的研究首次提供了证据，证明INSM1对乳腺癌肿瘤形成和生长的作用。此外，我们发现INSM1在乳腺癌发生发展过程中通过与SKP2相互作用正向调节C-MYC和p-ERK通路。总的来说，这些发现突出了INSM1作为乳腺癌治疗有前景的靶点。
