BRCA is a common malignant tumor distinguished by its aggressive nature and poor prognosis. The medical community is still looking toward novel and effective methods for diagnosis and treatment. Cuproptosis, a type of regulated cell death, can potentially induce tumor cells, especially those in BRCA, to die. Cuproptosis is a method for diagnosing and treating BRCA, although its precise targets and techniques have not yet been fully elucidated. This study uses LASSO to create a predictive model for CRGs in BRCA to address this knowledge gap. A subsequent CIBERSORT analysis was conducted to assess the prognostic potential of the developed model, and the results showed a correlation between this model and immune infiltration in BRCA. This study suggests that the immune system plays a significant role in initiating cuproptosis and its effects on the tumor microenvironment. The synergistic effect of stigmasterol and barasertib on BRCA cells was another exciting study discovery. These findings suggest a novel combinational treatment strategy for BRCA.
Cuproptosis is a recently discovered programmed cell death. The association between cuproptosis and tumors has been investigated, and the associations between CRGs and various tumor characteristics across common cancer types have been investigated. Cuproptosis has been associated with c-Myc-mediated BRCA and is dysregulated in BRCA tissues [31]. A prognostic cuproptosis-related signature in BRCA has also been identified through studies, and it not only predicts patient outcomes but also sheds light on the immune microenvironment. According to these findings, cuproptosis may represent a novel target for diagnosis and treatment [32, 33]. We conducted difference analysis and Cox unifactor analysis for the two patient groups, trained the obtained genes through LASSO, and obtained the calculation formula for risk score, which was used as a prognosis prediction model for patients with cuproptosis. The cluster analysis was based on the expression levels of 13 CRGs in BRCA. ADAM9 is a member of the ADAM family of proteins, which is involved in several physiological and pathological processes, including the progression of cancer. According to studies, ADAM9 is overexpressed and associated with higher tumor development grade, positive lymph node status, and distant metastasis in triple-negative BRCA (TNBRCA) compared to non-TNBRCA. The motility, invasion, and proliferation of cancer cells are all promoted by ADAM9. Recent research has demonstrated that the gene signatures associated with cuproptosis in lower-grade gliomas contain ADAM9. Here, we performed a KM survival analysis and calculated the AUC value in the training and validation groups, respectively. This proved that the risk score of our prediction model was in high agreement with the actual prognosis of patients. Additionally, we used several methods to verify the practicability and reliability of the model in the training and validation groups.
The tumor immune microenvironment (TME), which comprises complex interactions between cellular and non-cellular elements, plays a crucial role in the advancement and progression of cancer [34]. Cancer cells, immune cells, stromal tissue, and extracellular matrix are all parts of the TME [35]. The immune system has a significant impact on the TME, and the condition of the immune system within the TME is essential for the prevention, development, and progression of tumors [36]. Significant correlations have been found between the immunological constituents of the TME and tumor development, recurrence, and metastasis [37]. Tumor progression and therapeutic response in BRCA are contacted by the TME [38]. The balance between pro- and anti-tumor immune responses determines whether the TME can promote and inhibit tumor growth. [39]. Understanding the TME and its role in tumor development and progression is crucial for immune-targeted cancer therapies to be as effective as possible. This study revealed significant variations in the infiltration of B cells, macrophages, NK cells, and T cells between cancer and normal groups and between the high-risk and low-risk groups. These investigations suggest that our prognostic model determines the clinical prognosis and, to a certain extent, the immune infiltration of tumor cells.
Targeted therapy, a type of cancer treatment, uses drugs to specifically target cancer growth and survival by focusing on certain genes, proteins, or the tissue environment involved [40]. Cancer cells can be targeted using various targeted drugs, including monoclonal antibodies, hormone therapy, and targeted therapy [41]. Trastuzumab, pertuzumab, trastuzumab deruxtecan, and other drugs are specific examples of targeted therapies used to treat BRCA. [42]. Targeted therapy does have some limitations, including the development of drug resistance, side effects, and expensive treatment. Additionally, only some types of BRCA, such as HER2-positive and hormone receptor-positive BRCA, respond to targeted therapy [43]. It is important to create novel targeted therapies to overcome these limitations and improve the effectiveness of BRCA treatment. A phytosterol exhibits anticancer properties against several cancer cell lines through multiple mechanisms. These mechanisms include inhibiting tumor cell proliferation, reducing tumor angiogenesis, and inducing cancer cell apoptosis. In human gastric cancer cells, stigmasterol effectively inhibits cell migration, induces cell cycle arrest, triggers mitochondrial-mediated apoptosis, and impedes the JAK/STAT signaling pathway, resulting in strong antitumor effects [44]. The potential clinical utility of phytosterols in cancer treatment is hampered by the lack of standardization and their limited pharmacological action. Conversely, leukemia, colorectal cancer, and BRCA all exhibit a dose-dependent reduction of cell proliferation in vivo when treated with the Aurora kinase B inhibitor barasertib. Barasertib has become well-known as a therapeutic drug after extensive research in numerous tumor types. However, drug toxicity affected approximately 25% of patients with solid tumor, with neutropenia being the most prevalent dose-limiting toxicity [45]. Additional research is required to determine the ideal dosage, effectiveness, and safety of barasertib in cancer therapy. Analysis of the sensitivity of many regularly used chemotherapeutic drugs revealed a positive correlation between risk score-related genes and sensitivity. Notably, the risk score showed a strong association with barasertib, suggesting that it may be an effective drug for treating the cuproptosis prognosis model. Additionally, a prognostic model using molecular docking and network pharmacology revealed that stigmasterol, a compound present in turmeric, targets the ADAM9 protein. Therefore, we selected stigmasterol, which had the strongest binding ability, and barasertib, the most sensitive drug, for combined use in vitro. The results revealed that the two drugs synergically inhibited BRCA cells. Our study identified a novel and reliable strategy for treating BRCA and a solid theoretical foundation for combining traditional Chinese medicine and Western medicine.