STAT Family of Transcription Factors in Breast Cancer: Pathogenesis and Therapeutic Opportunities and Challenges.

Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin's anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients. 

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Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy

Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

Simple Summary Triple-negative breast cancer (TNBC) cases constitute ~15% of breast cancer tumors. This subtype is characterized by the lack of hormone receptors, estrogen and progesterone, and HER2, and it is a more aggressive, metastatic, and recurrent subtype than others. The need to develop novel anti-TNBC drugs encourages scientists to direct studies to identify potential therapeutic molecular targets. Our study aimed to define the role of the secretory carrier membrane protein, SCAMP3, in TNBC, and its association with the epidermal growth factor receptor (EGFR), which is present in ~90% of tumors. We confirmed that SCAMP3 promotes cell proliferation and motility and is directly associated with EGFR redistribution and degradation. It also regulates the gene and protein expression of molecules from the EGFR and PDGFR pathways. Finally, SCAMP3 depletion delays the establishment of TNBC tumors. This study provides evidence for SCAMP3′s TNBC tumor-promoting role and its potential as a target therapy for this disease. Abstract Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, and lethal breast cancer subtype. To improve the survival of TNBC patients, it is essential to explore new signaling pathways for the further development of effective drugs. This study aims to investigate the role of the secretory carrier membrane protein 3 (SCAMP3) in TNBC and its association with the epidermal growth factor receptor (EGFR). Through an internalization assay, we demonstrated that SCAMP3 colocalizes and redistributes EGFR from the cytoplasm to the perinucleus. Furthermore, SCAMP3 knockout decreased proliferation, colony and tumorsphere formation, cell migration, and invasion of TNBC cells. Immunoblots and degradation assays showed that SCAMP3 regulates EGFR through its degradation. In addition, SCAMP3 modulates AKT, ERK, and STAT3 signaling pathways. TNBC xenograft models showed that SCAMP3 depletion delayed tumor cell proliferation at the beginning of tumor development and modulated the expression of genes from the PDGF pathway. Additionally, analysis of TCGA data revealed elevated SCAMP3 expression in breast cancer tumors. Finally, patients with TNBC with high expression of SCAMP3 showed decreased RFS and DMFS. Our findings indicate that SCAMP3 could contribute to TNBC development through the regulation of multiple pathways and has the potential to be a target for breast cancer therapy.

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SCAMP3 Regulates EGFR and Promotes Proliferation and Migration of Triple-Negative Breast Cancer Cells through the Modulation of AKT, ERK, and STAT3 Signaling Pathways

ABSTRACT Colon cancer is among the most prevalent gastrointestinal tumor types. The long noncoding RNA (lncRNA) T cell leukemia homeobox 1 neighbor (TLX1NB) is up-regulated in colorectal cancer (CRC). However, the functional role of this lncRNA in colon cancer remains unknown. In our study, we investigated the clinical significance of TLX1NB in colon cancer through bioinformatics analysis and explored its role in migration, invasion and metastasis of colon cancer cell with a series of experiments. Firstly, TLX1NB was up-regulated in colon cancer tissues and increased TLX1NB expression was significantly associated with advanced N stages. In wound healing assays and transwell assays, TLX1NB overexpression promoted HCT116 cell migration and invasion while TLX1NB knockdown inhibited SW620 cell migration and invasion. In vivo, TLX1NB knockdown suppressed pulmonary metastasis of SW620 cell and vimentin expression but increased E-cadherin expression. Then, TLX1NB overexpression enhanced signal transducer and activator of transcription 5A (STAT5A) phosphorylation and TLX1NB knockdown suppressed STAT5A phosphorylation. Moreover, the inhibition of STAT5A phosphorylation reversed TLX1NB overexpression-associated increase in HCT116 cell migratory and invasive activity. In conclusion, TLX1NB enhances STAT5A phosphorylation to promote colon cancer cell invasion, migration, and metastasis. Graphical abstract

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2068781?needAccess=true

The long non-coding RNA T cell leukemia homeobox 1 neighbor enhances signal transducer and activator of transcription 5A phosphorylation to promote colon cancer cell invasion, migration, and metastasis

Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

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STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1.

Drug resistance is a daunting challenge in the treatment of breast cancer, making it an urgent problem to solve in studies. Cell lines are important tools in basic and preclinical studies; however, few breast cell lines from drug-resistant patients are available. Herein, we established a novel HER2-positive breast cancer cell line from the pleural effusion of a drug-resistant metastatic breast cancer patient. This cell line has potent proliferative capability and tumorigenicity in nude mice but weak invasive and colony-forming capability. The molecular subtype of the cell line and its sensitivity to chemotherapeutics and HER2-targeting agents are different from those of its origin, suggesting that the phenotype changes between the primary and metastatic forms of breast cancer.

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Wenying Zhuo

Papers

STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1.

Establishment and Characterization of a HER2-Positive Cell Line Derived From the Pleural Effusion of a Drug-Resistant Breast Cancer Patient