ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is a type of breast cancer that is characterized by the lack of expression of estrogen and progesterone receptors, and epidermal growth factor receptor 2. Therefore, there is an absence of a specific target for effective therapy in TNBC. Cisplatin is usually employed as a first-line chemotherapy agent for patients with TNBC. However, resistance remains an obstacle for cisplatin-based chemotherapy, due to its elusive underlying mechanism. Previously, abnormal expression of Islet 1 (ISL1) was demonstrated to be closely associated with cancer development and progression. The present study revealed that (ISL1) was significantly upregulated in TNBC tissues in comparison with adjacent normal tissues. Overexpression of ISL1 markedly promoted the proliferation and invasion of the TNBC MDA-MB-231 and MDA-MB-468 cell lines, while knockdown of ISL1 inhibited cell invasion and proliferation in these cell lines. In addition, overexpression of ISL1 reversed cisplatin-induced cell apoptosis, while knockdown of ISL1 enhanced apoptosis following cisplatin treatment in MDA-MB-231 and MDA-MB-468 cells. Furthermore, the levels of the anti-apoptotic proteins, phosphorylated-protein kinase B and B-cell lymphoma-2 (Bcl-2), were significantly decreased, while the levels of the pro-apoptotic protein Bcl-2-associated X protein were remarkably increased in response to cisplatin treatment. The present study revealed that ISL1 overexpression reversed the protein expression profile of p-Akt, Bcl-2 and Bax, while ISL1 knockdown promoted cell apoptosis. Therefore, the data of the present study demonstrated that ISL1 contributes to TNBC progression and reverses cell sensitivity towards cisplatin in TNBC cells, suggesting that ISL1 is a potential therapeutic target for the treatment of TNBC.

Super-Enhancer Redistribution as a Mechanism of Broad Gene Dysregulation in Repeatedly Drug-Treated Cancer Cells

“…SE regulators are known to act cooperatively (Hnisz et al, 2013;Lové n et al, 2013;Whyte et al, 2013) and likely do so also with ISL1, which may explain some of the inconsistent observed effects in the CRISPRi/a systems. A role of ISL1 in therapy resistance has been suggested in triple-negative breast cancer (TNBC) cells, in which ISL1 overexpression inhibits cisplatininduced cell apoptosis (Zhang et al, 2018). Other developmental transcription factors are also known to participate in cell survival in cancer cells, collectively known as ''lineage survival'' oncogenes, e.g., MITF (Garraway et al, 2005) and NKX2.1, SOX2, and CDX2 (Bass et al, 2009;Salari et al, 2012;Weir et al, 2007).…”

<p>TGF-β-Induced TMEPAI Attenuates the Response of Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel</p>

“…47 Islet-1 overexpression was reported to reduce TNBC cell response to cisplatin. 47,48 In the cells that have limited response to cisplatin, the role of TMEPAI is not prominent.…”

ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma

“…Compared with normal tissues, ISL1 is significantly upregulated in various cancers. ISL1 is involved in caner progression and is considered as a prognostic factor of multiple cancers [ 11 – 18 ]. In this study, we identified ISL1 as a novel oncogene acting through activation of PI3K/AKT signaling pathway in NB.…”

“…Recently, ISL1 has been reported to play crucial roles in cancer progression, and this is mainly based on an aberrant expression of ISL1. ISL1 was involved in triple-negative breast cancer, melanoma, and gastric cancer progression [ 11 – 13 ], and it was highly expressed in non-Hodgkin lymphoma compared to normal lymph nodes or Hodgkin lymphoma [ 14 ]. Besides, ISL1 was also verified to be a novel regulator of the cyclin D1 and c-Myc genes in cancer [ 15 ], and it could predict prognostics for cancers like gastric cancer, bladder cancer, and may also act as a biomarker in NB [ 13 , 16 – 18 ].…”