Open questions, current challenges, and future perspectives in targeting human epidermal growth factor receptor 2-low breast cancer

Curigliano, G.; Dent, R.; Earle, H.; Modi, S.; Tarantino, P.; Viale, G.; Tolaney, S.M.

doi:10.1016/j.esmoop.2024.102989

ESMO Open

2024

DOI: 10.1016/j.esmoop.2024.102989

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Open questions, current challenges, and future perspectives in targeting human epidermal growth factor receptor 2-low breast cancer

G. Curigliano,

R. Dent,

H. Earle

et al.

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2024

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Cited by 4 publications

References 107 publications

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HER2-low gastric cancer: is the subgroup targetable?

Shimozaki,

Fukuoka,

Ooki

et al. 2024

ESMO Open

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HER2-low gastric cancer: is the subgroup targetable?

Shimozaki,

Fukuoka,

Ooki

et al. 2024

ESMO Open

View full text Add to dashboard Cite

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation

Gu,

Xu,

et al. 2024

CPD

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Background: Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. Methods: Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. Results: The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties’ markers, KLF4 and OCT4, in these cell lines. Conclusion: Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.

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The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

Park,

Nam,

Kim

et al. 2024

Cancers

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TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed.

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Open questions, current challenges, and future perspectives in targeting human epidermal growth factor receptor 2-low breast cancer

Cited by 4 publications

References 107 publications

HER2-low gastric cancer: is the subgroup targetable?

HER2-low gastric cancer: is the subgroup targetable?

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

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