BackgroundTriple-negative breast cancer (TNBC) remains clinically challenging due to its aggressive nature, high recurrence rate, and lack of targeted therapies. To address these limitations, combination chemotherapies t...BackgroundTriple-negative breast cancer (TNBC) remains clinically challenging due to its aggressive nature, high recurrence rate, and lack of targeted therapies. To address these limitations, combination chemotherapies that synergistically enhance antitumor efficacy while permitting dose reduction and supporting dose-sparing strategies are urgently needed. Cisplatin has a broad spectrum of anticancer activity. However, its resistance and dose-limiting toxicities constrain clinical benefit. Digitoxin is a cardiac glycoside that has anticancer activity.ObjectiveWe aimed to assess the nature of interaction between digitoxin and cisplatin in TNBC cells, define the most synergistic area (MSA), and estimate dose-sparing potential.MethodsWe profiled digitoxin-cisplatin effects in MDA-MB-231 TNBC cell line by checkerboard and fixed-ratio designs, quantifying interaction with Chou-Talalay combination index/dose-reduction index by CompuSyn, and multiple matrix models by SynergyFinder.ResultsThe CI analysis demonstrated synergy across all tested ratios, with the strongest synergistic interaction at a digitoxin/cisplatin ratio of 1:200 (CI = 0.30 at ED). Dose-reduction analysis showed up to 27-fold cisplatin sparing (ratio 1:25, ED). Matrix-based models confirmed synergy (Bliss 6.9, Loewe 18.6, ZIP 7.1, and HSA 14), converging on MSA at 31.25 nM digitoxin and 6.25 µM cisplatin.ConclusionOur results highlight a robust synergistic interaction between digitoxin and cisplatin in MDA-MB-231 cells with a dosing window that maximizes cytotoxic effect while potentially reducing cisplatin exposure.
BackgroundTumour biomarkers have become increasingly important in oncology, shaping cancer diagnostics, classification, and patient management. Despite their potential, the use of cancer biomarkers in clinical settings r...BackgroundTumour biomarkers have become increasingly important in oncology, shaping cancer diagnostics, classification, and patient management. Despite their potential, the use of cancer biomarkers in clinical settings remains limited.ObjectiveThis paper aims to outline biomarker development, from classical, serum protein markers to emerging tumour biomarkers, including meta-biomarkers, to show their diversity and point out the challenges in their development, reporting, and implementation in clinical practice as well as their relevance in evidence-based pathology and cancer classification.MethodsA literature-based analysis, incorporating insights from our ongoing research, is presented.ResultsAlthough numerous potential biomarkers, biomarker signatures, and meta-biomarkers, are being discovered, existing innovations are often not supported by sufficiently rigorous research methodologies and standardised reporting practices to enable their translation into clinical practice.ConclusionsTo ensure that biomarker discoveries are both scientifically sound and clinically useful, improved research and validation methods, along with adherence to established reporting standards, are essential. We propose the use of the Hierarchy of Evidence for Tumour Pathology as a framework to evaluate and map existing evidence and identify knowledge gaps and research priorities.
BackgroundIn recent years, the significance of sirtuins in cancer biology has become increasingly evident, but their molecular mechanisms and prognostic impacts remain elusive.ObjectiveThe present study aimed to investig...BackgroundIn recent years, the significance of sirtuins in cancer biology has become increasingly evident, but their molecular mechanisms and prognostic impacts remain elusive.ObjectiveThe present study aimed to investigate the differential expression of the sirtuin gene family across cancers and to evaluate their prognostic value.MethodsWe used various bioinformatics databases and methodologies, including Oncomine, GEPIA, OncoDB, cBioPortal, R2 Kaplan-Meier Scanner, STRING, etc., to determine the expression pattern of the sirtuin family genes, along with their mutations and prognostic values in human cancers.ResultsIn the current study, , , , and were downregulated in lymphoma, whereas and were overexpressed. In breast cancer, , , and were overexpressed, and in terms of kidney cancer, higher expression of , , and was observed. In contrast, for leukemia, bladder, and brain cancers, most sirtuin family members showed reduced expression. We found that most mutations occurred in uterine cancer, chRCC (chromophobe renal cell carcinoma), DLBCL (diffuse large B-cell lymphoma), melanoma, pRCC (papillary renal cell carcinoma), and esophageal cancer. Moreover, we identified the relevant functional proteins through protein-protein interaction analysis to evaluate copy number alterations (CNAs) in sirtuins. The most frequent alterations were amplifications and deep deletions. Survival analysis demonstrated that and overexpression correlated with improved overall survival in low-grade glioma but predicted poorer outcomes in ovarian cancer. Downregulation of , , and was associated with better prognosis in DLBCL, while and upregulation predicted favorable survival in testicular germ cell tumors. overexpression was linked to favorable prognosis in esophageal carcinoma and sarcoma, while unfavorable outcomes were observed in hepatocellular carcinoma and cholangiocarcinoma. upregulation was significantly associated with reduced survival in esophageal, liver, and uterine cancers, but surprisingly correlated with improved outcomes in urothelial carcinoma and cervical squamous cell carcinoma.ConclusionsTogether, this multi-omics analysis reveals the correlation and prognostic values of sirtuins across multiple types of human cancers and suggests that sirtuins may serve as promising biomarkers for different cancers.
BackgroundOsteopontin is a glycophosphoprotein aberrantly expressed in several tumor types, which exhibits several isoforms generated by post-translational and post-transcriptional mechanisms, including alternative splic...BackgroundOsteopontin is a glycophosphoprotein aberrantly expressed in several tumor types, which exhibits several isoforms generated by post-translational and post-transcriptional mechanisms, including alternative splicing. Among total osteopontin (tOPN), the osteopontin-c (OPN-c) splice variant has been the most explored with an oncogenic role described for a range of tumor types. Especially in ovarian cancer (OC) cells, OPN-c is found overexpressed, presenting both diagnostic and prognostic implications.ObjectiveIn this review article, we aim to outline OPN-c roles in cancer, particularly in OC, in which it has been reported as a diagnostic biomarker.MethodsWe used PubMed search, and experimental procedures were summarized at the Figure legends.ResultsWe identified cytoplasmic, perinuclear, and nuclear OPN-c in OC cells that overexpress this OPN splice variant. Moreover, we report that OPN-c splicing isoform is found highly expressed in endometrioid OC patients' samples, compared to non-neoplastic ovarian tissues. Also, OPN-c expression levels have been associated with worse overall survival and worse progression-free survival in patients with both endometrioid and serous OC. Furthermore, OPN-c may be involved in a wide range of tumor features evoked by signaling pathways, such as AKT, ERK, and FAK.ConclusionsTherefore, a better comprehension of OPN-c roles in OC can further contribute to its application as a biomarker as well as a target for putative treatment strategies, especially those aiming to sensitize tumor cells to chemotherapeutic agents currently used in the OC treatment.
BackgroundMigrating strategies of the triple-negative breast cancer (TNBC) together with its role in the establishment of tumor microenvironment (TME), supporting metastasis, have been extensively studied. Extracellular...BackgroundMigrating strategies of the triple-negative breast cancer (TNBC) together with its role in the establishment of tumor microenvironment (TME), supporting metastasis, have been extensively studied. Extracellular matrix (ECM) is a major player for the TME, establishing the 3D spatial networks with interconnected pores necessary for the mechano-physiological function of the cells. Certain collagen aligners and cross-linkers which are necessary for the formation and the stabilization of ECM networks, however, have not been studied either in normal or in abnormal tissues. Complexities in cell-cell and cell-matrix interactions, and different in types and ratios of ECM proteins in a TME challenge to reveal the precise function of a particular protein that is exhibited by special cells and if specifically present in insignificant amount. Cancer-associated fibroblasts (CAFs) predominantly occupy the major stroma of a solid tumor where they deposit extracellular proteins in the excessive amount compared to other tumor-associated cells. For example, the TNBC tumor itself is positive for asporin (ASPN) since CAFs are major ASPN exhibitors. However, the TNBC cells express it insignificantly.ObjectiveThe increase in ECM and its networks suppresses the metastasis.MethodsHere, we studied the expression of collagen type I and ASPN in CAFS and MDA-MB-231 (MM231), and evaluated the role of ASPN in collagen alignment and crosslinking.ResultsTNBC cells have an insignificant expression of ASPN and scanty collagen fibers, some of which aggregate to form the stiff deranged fibers, forming large-size pores in ECM of cancer-cell-dominant outer core of TNBC that support cancer cell invasion and metastasis. Exogenous ASPN and fibroblast-ASPN supported for the collagen alignment and crosslinking that established the small-size pores in the ECM, inhibiting the cancer cell invasion.ConclusionsThe collagen aligner and the cross-linker, ASPN increases the ECM networks and decreases the migration, and this preliminary study provides the hope that ASPN might be used as an anti-metastatic drug after its confirmation through extensive studies in animal, and positive outcomes through preclinical trials.
BackgroundImmune checkpoint inhibitors (ICIs) provide a significant survival benefit in non-small cell lung cancer (NSCLC) patients; however, accurately predicting which patients will benefit remains a challenge. As prev...BackgroundImmune checkpoint inhibitors (ICIs) provide a significant survival benefit in non-small cell lung cancer (NSCLC) patients; however, accurately predicting which patients will benefit remains a challenge. As previously shown, the STOP model, a machine learning model based on serum tumor markers, is capable of identifying non-responders after 6 weeks of ICIs.ObjectiveThis study aims to externally validate this model and to assess the predictive value in combination with radiological response assessment using RECIST criteria.MethodsIn a cohort of 242 metastatic NSCLC patients, CYFRA, CEA, and NSE were measured before start and after 6 weeks of ICI treatment. The ability of the STOP model to predict no durable benefit (NDB; progressive disease, death within 6 months or disease control of less than 6 months) was assessed using specificity and positive predictive value (PPV). Moreover, a combination of the STOP model with RECIST after 6-8 weeks of ICIs was investigated.ResultsThe STOP model achieved a specificity of 96% (95% CI 95%-97%) and a PPV of predicting NDB of 88.1% (95% CI 85.9%-90.3%). Combining the STOP model with RECIST improved specificity and PPV to 100% and predicted NDB on average 11.6 weeks (IQR 1.8-18.0 weeks) prior to developing radiologically defined progression.ConclusionsAfter 6 weeks of ICIs, the blood-based STOP model was capable of accurately predicting NDB in metastatic NSCLC patients, earlier than conventional radiological assessment. The combined serological and radiological response assessment creates an early opportunity to safely stop ICI treatment in patients who will not benefit, although the clinical utility of the assay is limited since the high specificity comes at the cost of a lower sensitivity.
BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is among the vital pro-inflammatory cytokines that potentially exerts a significant influence on the immune response, hence potentially regulating the advancement of cervic...BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is among the vital pro-inflammatory cytokines that potentially exerts a significant influence on the immune response, hence potentially regulating the advancement of cervical lesions. OBJECTIVE: Our study objective was to examine the relationship between two single nucleotide polymorphisms (SNPs) (rs1799724 and rs1800629) of TNF-α and the risk of cervical cancer in women from Bangladesh. METHODS: We recruited 133 patients with cervical cancer and 126 healthy individuals for this study. Genotyping was performed using real-time PCR SNP genotyping assay. Multivariate logistic regression analysis was used to determine the odds ratio (OR) along with 95% confidence intervals (CI) and p-values. RESULTS: For rs1799724 (C > T) polymorphism, TT mutant homozygous genotype carried 3.26 times increased risk of developing cervical cancer (OR = 3.26, 95% CI = 1.15-9.28, p = 0.027). Polymorphism of rs1800629 (G > A) was also related to an elevated risk of cervical cancer. Individuals with the AG heterozygous genotype (OR = 2.85, 95% CI = 1.20-6.74, p = 0.017) and AA mutant homozygous genotype (OR = 4.55, 95% CI = 1.24-16.60, p = 0.022) also had a higher likelihood of having cervical cancer. Moreover, we found that injectable contraceptives increase the risk of cervical cancer. Individuals who smoked and/or had first-degree relatives with cancer were more likely to carry the risk allele, which increases the likelihood of developing cervical cancer. CONCLUSION: TNF-α polymorphisms in rs1799724 and rs1800629 increase the susceptibility of developing cervical cancer in women from Bangladesh.
BACKGROUND: It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported...BACKGROUND: It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types. OBJECTIVE: The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens. METHODS: The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique. RESULTS: MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (P = 0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (P = 0.009) and CRA cases (P = 0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (P = 0.050) and perineural invasion (P = 0.017). CONCLUSIONS: Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.
Clinical laboratories are responsible for performing lung cancer tumor marker testing as part of routine clinical care. It is their responsibility to guarantee that the reported tumor marker results are reliable and mee... Clinical laboratories are responsible for performing lung cancer tumor marker testing as part of routine clinical care. It is their responsibility to guarantee that the reported tumor marker results are reliable and meet the necessary quality standards for proper clinical use. During the different laboratory phases, pre-analytical, analytical and post-analytical, specific steps and processes can introduce errors and generate incorrect clinical interpretation. This editorial briefly outlines critical laboratory issues related to lung cancer tumor markers, specific for each of these three laboratory phases.
Blood-based diagnostics for lung cancer support the diagnosis, estimation of prognosis, prediction, and monitoring of therapy response in lung cancer patients. The clinical utility of serum tumor markers has considerably...Blood-based diagnostics for lung cancer support the diagnosis, estimation of prognosis, prediction, and monitoring of therapy response in lung cancer patients. The clinical utility of serum tumor markers has considerably increased due to developments in serum protein tumor markers analytics and clinical biomarker studies, the exploration of preanalytical and influencing conditions, the interpretation of biomarker combinations and individual biomarker kinetics, as well as the implementation of biostatistical models. In addition, circulating tumor DNA (ctDNA) and other liquid biopsy markers are playing an increasingly prominent role in the molecular tumor characterization and the monitoring of tumor evolution over time. Thus, modern lung cancer biomarkers may considerably contribute to an individualized companion diagnostics and provide a sensitive guidance for patients throughout the course of their disease. In this special edition on Tumor Markers in Lung Cancer, experts summarize recent developments in clinical laboratory diagnostics of lung cancer and give an outlook on future challenges and opportunities.
Trapé J, Fernández-Galán E, Auge JM
… +5 more, Carbonell-Prat M, Filella X, Miró-Cañís S, González-Fernández C, Oncology Biomarkers Section of the Catalan Association of Clinical Laboratory Science
BACKGROUND: Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce...BACKGROUND: Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce the synthesis of TMs, and the release of these molecules into the bloodstream allows their quantification in biological fluids. Although very small concentrations of TMs are usually present in the serum or plasma of healthy subjects, increased concentrations may also be found in the presence of benign diseases or due to technical interference, producing false positive results. MATERIAL AND METHODS AND RESULTS: Our review analyses the causes of false positives described between January 1970 to February 2023 for the TMs most frequently used in clinical practice: α-fetoprotein (AFP), β2-microglobulin (β2-M), cancer antigen 15-3 (CA 15-3), cancer antigen CA 19-9 (CA 19-9), cancer antigen CA 72-4 (CA 72-4), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), chromogranin A (CgA), choriogonadotropin (hCG), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), human epididymis protein 4 (HE4), serum HER2 (sHER2), squamous cell carcinoma antigen (SCCA), protein induced by vitamin K absence-II (PIVKA-II), Pro-gastrin-releasing peptide (Pro-GRP), prostate-specific antigen (PSA), Protein S-100 (S-100) and thyroglobulin (Tg). A total of 247 references were included. CONCLUSIONS: A better understanding of pathophysiological processes and other conditions that affect the concentration of TMs might improve the interpretation of results and their clinical application.
BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction...BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction and monitoring of therapy response in NSCLC patients receiving chemotherapy. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on 261 advanced NSCLC patients, CYFRA 21-1, CEA, SCC, NSE, ProGRP, CA125, CA15-3 and HE4 were assessed in serial serum samples and correlated with radiological response after two cycles of chemotherapy and overall (OS) and progression-free survival (PFS). RESULTS: While pretherapeutic STM levels at staging did not discriminate between progressive and non-progressive patients, CYFRA 21-1, CA125, NSE and SCC at time of staging did, and yielded AUCs of 0.75, 0.70, 0.69 and 0.67 in ROC curves, respectively. High pretherapeutic CA15-3 and CA125 as well as high CYFRA 21-1, SCC, CA125 and CA15-3 levels at staging were prognostic for shorter PFS and OS -also when clinical variables were added to the models. CONCLUSIONS: STM at the time of first radiological staging and pretherapeutic CA15-3, CA125 are predictive for first-line treatment response and highly prognostic in patients with advanced NSCLC.
BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of...BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76-0.87), 0.78 (0.73-0.84), and 0.88 (0.84-0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90-0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81-0.91), 0.80 (0.74-0.85), and 0.85 (0.79-0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89-0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84-0.94) and 0.96 (0.93-0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95-0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81-0.91), NSE (AUC 0.83; 0.78-0.88) and CYFRA 21-1 (AUC 0.69; 0.64-0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91-0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes.
BACKGROUND: Programmed cell death receptors and ligands in cancer tissue samples are established companion diagnostics for immune checkpoint inhibitor (ICI) therapies. OBJECTIVE: To investigate the relevance of soluble P...BACKGROUND: Programmed cell death receptors and ligands in cancer tissue samples are established companion diagnostics for immune checkpoint inhibitor (ICI) therapies. OBJECTIVE: To investigate the relevance of soluble PD-1, PD-L1 and PD-L2 for estimating therapy response and prognosis in non-small cell lung cancer patients (NSCLC) undergoing platin-based combination chemotherapies. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on advanced NSCLC patients, soluble PD-1, PD-L1 and PD-L2 were assessed in serial serum samples by highly sensitive enzyme-linked immunosorbent assays and correlated with radiological response after two cycles of chemotherapy and with overall survival (OS). RESULTS: Among 243 NSCLC patients, 185 achieved response (partial remission and stable disease) and 58 non-response (progression). The distribution of PD-1, PD-L1 and PD-L2 at baseline (C1), prior to staging (C3) and the relative changes (C3/C1) greatly overlapped between the patient groups with response and non-response, thus hindering the discrimination between the two groups. None of the PD markers had prognostic value regarding OS. CONCLUSIONS: Neither soluble PD-1, PD-L1 nor PD-L2 did provide clinical utility for predicting response to chemotherapy and prognosis. Studies on the relevance of PD markers in ICI therapies are warranted.
BACKGROUND: Hotspot mutations occurring in the p110α domain of the PIK3CA gene, specifically p110αH1047R/L increase tumor metastasis and cell motility in triple-negative breast cancer (TNBC). These mutations also affect...BACKGROUND: Hotspot mutations occurring in the p110α domain of the PIK3CA gene, specifically p110αH1047R/L increase tumor metastasis and cell motility in triple-negative breast cancer (TNBC). These mutations also affect the transcriptional regulation of ΔNp63α, a significant isoform of the p53 protein involved in cancer progression. This study attempts to investigate the transcriptional impact of p110αH1047R/L mutations on the PIK3CA/ΔNp63α complex in TNBC carcinogenesis. METHODS: We performed site-directed mutagenesis to introduce p110αH1047R/L mutations and evaluated their oncogenic effects on the growth, invasion, migration, and apoptosis of three different TNBC cell lines in vitro. We investigated the impact of these mutations on the p110α/ΔNp63α complex and downstream transcriptional signaling pathways at the gene and protein levels. Additionally, we used bioinformatics techniques such as molecular dynamics simulations and protein-protein docking to gain insight into the stability and structural changes induced by the p110αH1047R/L mutations in the p110α/ΔNp63α complex and downstream signaling pathway. RESULTS: The presence of PIK3CA oncogenic hotspot mutations in the p110α/ΔNp63α complex led to increased scattering of TNBC cells during growth, migration, and invasion. Our in vitro mutagenesis assay showed that the p110αH1047R/L mutations activated the PI3K-Akt-mTOR and tyrosine kinase receptor pathways, resulting in increased cell proliferation, invasion, and apoptosis in TNBC cells. These mutations decreased the repressing effect of ΔNp63α on the p110α kinase domain, leading to the enhancement of downstream signaling pathways of PI3K and tyrosine kinase receptors and oncogenic transformation in TNBC. Additionally, our findings suggest that the physical interaction between the DNA binding domain of ΔNp63α and the kinase domain of p110α may be partially impaired, potentially leading to alterations in the conformation of the p110α/ΔNp63α complex. CONCLUSION: Our findings suggest that targeting the p110αH1047R/L mutations in TNBC could be a promising strategy for developing transcriptional-based therapies. Restoring the interaction between ΔNp63α and the p110α kinase domain, which is disrupted by these mutations, may provide a new approach to treating TNBC.