Breast Cancer : Targets and Therapy最新文献

Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Rho-associated coiled-coil containing protein kinase (ROCK) signaling is a promising target, known to drive tumor progression through cytoskeletal remodelling and epithelial-mesenchymal transition (EMT). However, its role in disrupting epithelial integrity via adherens and tight junctions in TNBC remains underexplored. Fasudil-D-6h is a novel derivative of the clinically approved ROCK inhibitor fasudil. This study investigates the anti-tumor efficacy of fasudil-D-6h and its novel mechanism of action in TNBC.

Methods: The effects of fasudil-D-6h and the reference inhibitor HA-1100 on cell proliferation (CCK-8) and apoptosis (flow cytometry) were assessed in MDA-MB-231 and MCF-7 cells. Transcriptome sequencing of fasudil-D-6h-treated MDA-MB-231 cells identified differentially expressed genes (DEGs) and enriched pathways. A protein-protein interaction (PPI) network was constructed. The in vivo efficacy was evaluated in a nude mouse model of subcutaneous MDA-MB-231 tumors. qRT-PCR and Western blotting validated the expression of ROCK1/2 and key adherens junction pathway components (Cdc42, Rac3, Src, ZO-1, Occludin, Claudin-1).

Results: Fasudil-D-6h significantly inhibited proliferation and induced apoptosis in TNBC cells. Transcriptomic analysis revealed 8,092 DEGs, with significant enrichment in the adherens junction pathway. Accordingly, fasudil-D-6h treatment in vitro and in vivo significantly downregulated ROCK1/2 and robustly upregulated the expression of CDC42, RAC3, SRC, ZO-1, OCCLUDIN, and CLAUDIN-1. In the mouse model, fasudil-D-6h treatment led to a significant reduction in tumor mass and volume.

Discussion: Our findings demonstrate that the novel ROCK inhibitor fasudil-D-6h exerts potent anti-tumor effects in TNBC. Its mechanism of action is distinctively linked to the restoration of genes critical to adherens and tight junction integrity. Given its derivation from the clinically viable fasudil, fasudil-D-6h presents a strong translational potential as a novel therapeutic agent for TNBC.

Introduction: Breast cancer is the second most common cancer among women worldwide. Estrogen is currently identified as one of the main agents involved in the initiation of breast tumors; however, evidence indicates a greater risk when estrogen replacement is combined with progesterone, whereas its isolated use does not represent a significant risk. Inconsistencies in existing theories highlight the need for further detailed research on the relationship between hormone exposure and breast tumorigenesis, with particular emphasis on fibrinogen and its components in the context of this review.

Objective: Introduce a new theory into the medical literature concerning the genesis of breast cancer.

Methods: This is an integrative literature review based on a selection of relevant articles published between 2000 and 2025, in both Portuguese and English, and sourced from the following databases: Scielo, ScienceDirect, National Library of Medicine, PubMed, Cochrane, Brazilian Journal of Development, and ResearchGate.

Results: Fifty-six references were selected to support the development of the discussion components, which are subdivided into the following themes: physiology of estrogen and progesterone in the body, actions of hormonal therapies, both combined and isolated, in breast cancer, and fibrinolytic physiology.

Conclusion: After identifying contradictions in current theories about the influence of estrogen on tumor proliferation, which encouraged the search for new interpretations, it was demonstrated that free estrogen and its by-products, such as fibrinogen-related protein (fibrinogen-like protein 1 and 2), play a role in the immune system's failure to contain malignant cells, opening another field of therapeutic research for breast cancer.

Background: Inetetamab is a Chinese-origin recombinant anti-HER2 monoclonal antibody. Herein, we assessed the efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer (MBC).

Patients and methods: We retrospectively reviewed the medical records of patients with HER2-positive MBC who received inetetamab-containing regimens as a salvage treatment in metastatic setting from December 2020 to April 2024. The primary endpoint was progression-free survival (PFS) in the total population (TP). Patients with brain metastases were also included. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety.

Results: At the data cut-off date of June 1, 2024, a total of 90 patients were included in this analysis. Median follow-up duration was 7.2 months (IQR 3.6-13.1). The median PFS was 12.0 months (95% confidence interval [CI] 7.3 to 17.0 months) in the TP. The median PFS in the subgroup with brain metastases reached 10.0 months (95% CI 5.9 to NA months). The ORR was 46.6% (42/90), and the DCR was 92.2% (83/90). The most frequently combined chemotherapy was vinorelbine (83/90,92.2%). The most frequently concomitant targeted drug was pyrotinib (70/90,77.8%). The median PFS not reached for first-line, 15.9 months (95% CI 11.9 to NA months) for second-line, and 5.9 months (95% CI 4.4 to 12.2 months) for third-line or later therapy. Cox univariate and multivariate analyses demonstrated that lines of treatment were the only significant predictive factor for PFS (first- and second-line vs third-line or above: 15.9 vs 5.9 months, p=0.0021). The toxicity was tolerable. The most frequent grade 3 or 4 treatment-related adverse events were diarrhea (12.2%).

Conclusion: Inetetamab offers a promising option and a manageable safety profile for HER2-positive MBC who pretreated with multiple-line therapies. Meanwhile, inetetamab plus small-molecule TKIs regimens shows good anti-tumor efficacy for MBC with brain metastases, which deserves further validation in a larger group trial.

Purpose: BEND3 is implicated in various physiological processes, including chromatin regulation, cell cycle regulation, etc.; nonetheless, its function in cancer is not well comprehended.

Methods: Using public databases including UCSC Xena, TCGA, GTEx, and GEO, we conducted a comprehensive pan-cancer analysis to evaluate the clinical relevance of BEND3 across 33 cancer types. We analyzed genetic alterations, copy number variations (CNVs), and methylation profiles of BEND3, and explored its associations with tumor mutational burden (TMB), microsatellite instability (MSI), immune checkpoint molecules, and the tumor immune microenvironment. A protein-protein interaction (PPI) network and functional enrichment analysis were performed to investigate potential molecular mechanisms. In vitro, BEND3 expression was assessed by immunohistochemistry (IHC), Western blot (WB), and qRT-PCR. Cell Counting Kit-8 (CCK-8), colony formation, and wound healing assays were performed to validate BEND3's oncogenic role in breast cancer cell lines.

Results: Our results show that BEND3 is frequently overexpressed in multiple cancers, including breast, liver, lung, thyroid, and gastric cancers, among others, and is associated with poor prognosis. Its expression correlates with TMB, MSI, immune checkpoint molecules, and immunoinfiltration, suggesting a role in tumor immunity. Functional analysis indicates involvement in key cancer-related pathways. In breast cancer, BEND3 was upregulated in clinical tissues and cell lines, and in vitro experiments demonstrated that BEND3 overexpression promoted the proliferation, migration, and invasion of breast cancer cells, whereas its knockdown suppressed these phenotypes.

Conclusion: Our findings suggest BEND3 is a potential prognostic and immune-related cancer biomarker. Its overexpression in multiple cancers, association with poor survival, and role in tumor immunity support its oncogenic function. Functional analysis indicates it may regulate key cancer pathways. Importantly, in vitro experiments confirm its tumor-promoting effects in breast cancer, providing a foundation for further study of BEND3's mechanisms and therapeutic implications.

Breast cancer (BC) is the most common cause of deaths. Although recent medical advancements have improved survival of BC patients, the occurrence of metastasis increases mortality rate. Noncoding RNAs (ncRNAs) play important roles in BC metastasis (BCM). However, a detailed summary of ncRNAs involved in BCM is unavailable. Therefore, this review summarizes the key biological steps involved in BCM. We discussed the ncRNAs related to BCM according to "seed and soil" theory from four perspectives: (i) ncRNAs that make "breast cancer seed" preferable for BCM; (ii) ncRNAs that make "breast cancer seed" difficult for BCM; (iii) ncRNAs that make "breast cancer soil" preferable for BCM; (iv) ncRNAs that make "breast cancer soil" difficult for BCM. Lastly, we listed the ncRNAs and coding genes involved in BCM that act as initiators or suppressors. This review comprehensively overviews the biological mechanisms underlying BCM. The compiled evidence highlights the role of BCM-associated ncRNAs, which may serve as promising therapeutic targets for BCM.

Background: The Phase III INAVO120 trial established inavolisib-based therapy as a superior first-line treatment for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, a finding of particular importance for the historically underrepresented male population with high unmet need.

Methods: A lifetime Markov model was developed from a US payer perspective to evaluate the cost-effectiveness of inavolisib plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in men with PIK3CA-mutated advanced breast cancer. Primary outcomes were life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).

Results: The inavolisib group provided an additional 1.23 LYs and 0.69 QALYs compared to the placebo group, resulting in an ICER of $886,440 per QALY. One-way sensitivity analysis identified the price of inavolisib as the primary driver of the ICER. Probabilistic sensitivity analysis showed a 0% probability of inavolisib being cost-effective at a willingness-to-pay threshold of $150,000 per QALY.

Conclusion: Inavolisib-based therapy is not cost-effective for treating PIK3CA-mutated advanced male breast cancer at its current price. Significant price reductions or adjustments to value assessment frameworks are required to ensure equitable access for this underserved population.

Purpose: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) exert strong immunosuppressive effects and are associated with poor prognosis in breast cancer. However, the mechanism underlying their differentiation remains unclear. Here, we aimed to elucidate how transforming growth factor-β1 (TGF-β1)/SMAD4 signaling regulates PMN-MDSC differentiation and modulates the breast cancer immune microenvironment.

Methods: We analyzed neutrophil subpopulation heterogeneity in breast cancer tissues using single-cell RNA sequencing combined with spatial transcriptomics (GSE176078 dataset). A 4T1 mouse breast cancer metastasis model was established, and tumor progression was tracked via in vivo fluorescence imaging. Colony formation and differentiation outcomes following Tgfb1 overexpression or knockdown were assessed in spleen-derived hematopoietic stem cells using flow cytometry. Gene expression profiles and signaling pathways were characterized using RNA sequencing and Western blotting.

Results: Neutrophil subpopulations in breast cancer tissues exhibited significant heterogeneity, particularly the N3 subset, which showed enhanced intracellular communication and regulatory potential. Tgfb1 was significantly upregulated along the neutrophil developmental trajectory in both spleen tissue and serum of breast cancer mice. In normal mice, the number of metastatic foci significantly correlated with neutrophil proportions. Tgfb1 overexpression promoted PMN-MDSC differentiation, colony formation, and SMAD4 upregulation in normal mice but exerted opposite effects in tumor-bearing mice.

Conclusion: Our findings implicate TGF-β1/SMAD4 signaling in the differential regulation of PMN-MDSC differentiation in breast cancer models. The TGF-β1 pathway represents a potential therapeutic target for modulating the immune microenvironment in breast cancer, although further validation in clinical settings is required to determine therapeutic efficacy.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, which limits targeted therapies. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are known to secrete factors that promote tumor progression. The role of neuregulin-1 (NRG1), a ligand of HER3 and HER4, in TNBC and its association with CAFs remains unclear.

Methods: We analyzed NRG1 mRNA and protein levels in TNBC tumor and adjacent tissues using qRT-PCR and ELISA, and evaluated their relationship with clinicopathological parameters and prognosis in 174 patients. Serum NRG1 levels were assessed via ELISA in TNBC patients and healthy controls. The effects of CAF-secreted NRG1 on TNBC cells were studied using conditioned medium, siRNA knockdown, and xenograft mouse models. Statistical analyses, including ROC curves and survival analyses, were performed to determine diagnostic and prognostic value.

Results: NRG1 expression was significantly upregulated in TNBC tissues and serum compared to controls, correlating with advanced TNM stages and poor prognosis. ROC analysis demonstrated diagnostic value of NRG1 in tissues and serum. CAFs secreted higher levels of NRG1 compared to normal fibroblasts. Conditioned medium from CAFs enhanced TNBC cell proliferation, migration, and MMP9 expression, effects reduced by NRG1 knockdown. In vivo, CAF-conditioned medium promoted tumor growth, while NRG1 knockdown reduced this effect.

Conclusion: Our findings suggest that CAF-secreted NRG1 is closely associated with TNBC progression and may represent a potential biomarker and therapeutic target, although further validation is needed to establish causality.

Triple negative breast cancer (TNBC) is characterized as an estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor (HER-2) negative disease with an enhanced systemic metastatic incidence, chemotherapeutic insensitivity, and drug resistance. The internal characteristics of TNBC are extraordinary complex and are accompanied by numerous gene mutations and constitutively activated signaling networks, which, in turn, augment TNBC malignancy. There is an urgency to uncover new and potent therapeutic targets for TNBC. Herein, we discussed the historical as well as newly discovered subtypes and properties of TNBC. We also presented a systematic outline of the aberrant gene expression and abnormal activated signaling networks in TNBC. Subsequently, we summarized the corresponding targeted therapeutic drugs, and reviewed the current targeted TNBC therapies launched in clinical trials, thereby providing a direction for future TNBC therapy. We also provided a detailed list of coding genes involved in chemo-sensitive and chemo-resistance of TNBC, which can potentially serve as indicators of chemotherapeutic efficacy. Finally, we discussed the novel and future potential treatments of TNBC. This review highlighted the new era of TNBC treatment in the coming years and provided the gene expression profile of TNBC patients who may benefit from chemotherapy.

Purpose: This research aimed to ascertain the clinical implications of lncRNA CKMT2-AS1 and its underlying molecular mechanism in patients with breast cancer.

Patients and methods: CKMT2-AS1 expression were assessed in breast cancer. The prognostic implication of CKMT2-AS1 was evaluated using Cox regression analysis. Functional assays were conducted to explore the effects of CKMT2-AS1 on the cellular activities associated with breast cancer. Mechanistic investigations included dual-luciferase reporter assays, bioinformatics, and Western blot analyses to elucidate the molecular pathways involving CKMT2-AS1.

Results: The analysis revealed that CKMT2-AS1 was significantly reduced in breast cancer tissue specimens and cell lines (P<0.05). Its expression was correlated with advanced stages of tumors (P=0.031) and the presence of lymph node metastasis (P=0.044). The upregulation of CKMT2-AS1 led to an obvious decline in cell proliferation, migration, and invasion, while also enhancing apoptosis in breast cancer cells (P<0.05). Furthermore, mechanistic studies indicated that CKMT2-AS1 directly interacts with miR-106b-5p, a microRNA that is elevated in breast cancer, thereby influencing the expression of its target gene MECP2, which is recognized as a tumor suppressor.

Conclusion: CKMT2-AS1 exerts its tumor-suppressing function in breast cancer via sequestering miR-106b-5p and modulating MECP2 expression. Its decreased levels are linked to the unfavorable prognosis, positioning CKMT2-AS1 as a prospective indicator for prognosticating breast cancer.