Breast Cancer Research最新文献

Context and aims: Everolimus was approved in 2012 for the treatment of advanced hormone-receptor-positive, HER2-negative metastatic breast cancer (MBC) in combination with exemestane. Since then, the first line treatment for these cancers has evolved with the development of CDK4/6 inhibitors.

Methods: Patients with histologically proved MBC and who received everolimus between 2012 and 2022 were included in a multicentric retrospective cohort. Prior exposure to CDK4/6 inhibitors was documented. The purpose of the study was to evaluate the efficacy of everolimus plus endocrine therapy in patients previously treated with CDK4/6 inhibitors and to identify factors associated with improved PFS on everolimus. The primary endpoint was PFS. Secondary outcomes included overall survival (OS), factors associated with improved efficacy, and grade III-IV toxicities.

Results: From 2012 to December 30, 2022, 325 patients were included. Of these, 75 patients (23%) had been pretreated by CDK4/6 inhibitors. In the overall population, median PFS was 6.4 months (95% CI, 5.5-7.1), with a median OS of 25 months (95% CI, 21.8-28.1). Among those previously exposed to CDK4/6 inhibitors, median PFS was 5.3 months (95% CI, 4.6-7.1), compared to 6.7 months (95% CI, 5.8-7.6) for those who had not received CDK4/6 inhibitors (p = 0.046) and the median OS was 27.3 months without CDK4/6 inhibitors before everolimus (95% CI, 23.2-30.2) versus 21.8 months (95% CI,18.5-25.5) when pretreated by CDK4/6 inhibitors (p = 0.01). Sixty-eight patients (21%) had a PFS greater than 12 months. Factors associated with an improved PFS were the lack of liver metastases (p < 0.001), no prior exposure to metastatic chemotherapy (p = 0.001), a lower tumor grade (p = 0.005), no prior treatment with CDK4/6 inhibitors (p = 0.006), and a better performance status (p = 0.008). 89 patients (28%) discontinued everolimus due to toxicity rather than disease progression or death and 23 (25%) patients treated with exemestane alone, after everolimus exposure, maintained a stable disease for at least 6 months.

Conclusion: Patients who had prior exposure to CDK4/6 inhibitors experienced a shorter median PFS benefit from everolimus based-treatment compared to those who were CDK4/6 inhibitor-naive. In this study, they also demonstrated shorter OS, likely due to a more pronounced endocrine-resistant profile. Although a reduction in PFS is expected with successive lines of therapy, the use of everolimus after exposure to CDK4/6 inhibitors and aromatase inhibitors remains an option and allows to propose another endocrine-based therapy and to postpone the use of chemotherapy. Managing endocrine resistance remains challenging and further research is needed to identify predictive biomarkers for improved outcomes.

Background: Circulating tumor cell (CTC) clusters exhibit significantly greater metastatic potential than single CTCs and are associated with poorer overall survival in cancers. However, the molecular mechanisms driving CTC cluster formation remain unclear. p21-activated kinase 2 (PAK2) plays a critical role in cytoskeletal remodeling and is frequently associated with advanced tumor progression and poor prognosis. In this study, we explored the role of PAK2 in CTC cluster formation in breast cancer.

Methods: We performed an integrated bioinformatics analysis of transcriptomic profiles from single CTCs and CTC clusters via GEO datasets to identify differentially expressed genes (DEGs) and candidate hub genes associated with CTC clustering. Functional enrichment analyses and gene set enrichment analysis were subsequently conducted to explore relevant pathways. The biological function of the identified hub gene PAK2 was validated via in vitro CTC cluster formation cell models and in vivo orthotopic in situ breast cancer mouse models. Mechanistic studies focused on PAK2-mediated phosphorylation of E-cadherin. Additionally, the therapeutic potential of targeting PAK2 was evaluated via the use of the selective PAK inhibitor FRAX597 in vivo.

Results: Bioinformatics analyses revealed that CTC clusters are characterized by enhanced cell-cell adhesion, increased proliferative capacity and survival advantages. Among the identified hub genes, PAK2 was significantly upregulated in breast cancer tissues and cell lines, and its elevated expression was associated with poor patient prognosis. Functional experiments demonstrated that PAK2 promotes CTC cluster formation by increasing E-cadherin phosphorylation at Ser840, thereby strengthening cell-cell adhesion. Pharmacologic inhibition of PAK2 with FRAX597 impaired CTC cluster formation, suppressed tumor growth, reduced metastasis and decreased CTC cluster numbers in vivo.

Conclusions: This study revealed that PAK2 promotes CTC cluster formation and breast cancer metastasis by enhancing E-cadherin-mediated cell-cell adhesion. These results provide novel insights into the molecular mechanisms underlying CTC cluster formation and highlight PAK2 as a potential therapeutic target and diagnostic marker for preventing breast cancer metastasis.

Background: Triple negative breast cancer (TNBC), characterized by its aggressive clinical behavior and propensity for distant metastasis, presents critical challenges in therapeutic management. Emerging evidence implicates lipid metabolic reprogramming as a key facilitator of tumor progression and metastatic dissemination. However, the precise molecular mechanisms underlying lipid metabolic dysregulation in TNBC metastasis remain poorly characterized. Our work systematically elucidates the mechanistic role of ALDH3A2 in orchestrating lipid metabolic adaptations that drive breast cancer metastasis.

Methods: Transcriptomic analysis of clinical datasets identified metastasis-related metabolic regulators. Cellular migration/invasion assays and murine metastasis models were utilized to assess metastatic effects of ALDH3A2. Lipidomic profiling coupled with pathway analysis characterized metabolic alterations. Mechanistic studies integrated western blot analysis with lipid droplet quantification. Computational approaches including structure-based virtual screening and molecular docking simulations were employed for inhibitor discovery.

Results: ALDH3A2 was significantly upregulated in TNBC clinical specimens and showed significant association with adverse clinical outcomes. Functional validation confirmed that ALDH3A2 potentiates TNBC cell migration/invasion through epithelial-mesenchymal transition (EMT) activation. Metabolic profiling revealed ALDH3A2-driven lipid accumulation, evidenced by increased lipid droplet formation and elevated triglyceride levels. Specifically, arachidonic acid (AA) enrichment was observed in ALDH3A2-overexpressing cells, corresponding to enhanced glycerophospholipid metabolism. Mechanistic studies demonstrated that ALDH3A2-mediated AMP/ATP imbalance suppresses AMPK phosphorylation while activating mTOR/SREBP1 signaling. mTOR inhibition effectively attenuated ALDH3A2-induced lipid metabolic alterations. Importantly, oxaliplatin was identified as a potential therapeutic agent targeting ALDH3A2-mediated AA metabolism to suppress metastasis.

Conclusions: Our work establishes ALDH3A2 as a pivotal regulator of lipid metabolic reprogramming in TNBC metastasis, providing mechanistic insights into AA-mediated tumor progression. These findings position ALDH3A2 as a promising therapeutic target and prognostic biomarker for TNBC management.

Background: Cancer progression is driven by somatic mutations, with alterations in driver genes such as tumor suppressors and oncogenes playing critical roles. In breast cancer (BRCA), mutations in MAP3K1 and MAP2K4 are recurrent, especially in estrogen receptor-positive (ER⁺) subtypes, yet their functional significance and mechanistic contributions remain incompletely understood. This study aims to elucidate the role of MAP3K1/MAP2K4 mutations in BRCA pathogenesis.

Methods: We performed integrated genomic analyses using data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Functional validation was conducted in breast cancer cell lines (e.g., MCF-7, ZR-75-1) using shRNA-mediated knockdown, overexpression of dominant-negative MKK4 (MKK4DN), and western blotting. In vivo tumor growth and metastasis were assessed using a xenograft mouse model. Proteomic and phosphoproteomic data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to evaluate JNK pathway activity and FOSL1 expression across multiple cancer types.

Results: MAP3K1 and MAP2K4 were identified as frequently mutated in BRCA, with mutation spectra dominated by loss-of-function alterations. These mutations exhibited mutual exclusivity with TP53 alterations and were enriched in ER + tumors. Mechanistically, MAP3K1/MAP2K4 loss led to reduced JNK2 phosphorylation, impaired p53 activation at Ser15, and subsequent upregulation of FOSL1 (encoding FRA1), promoting tumor proliferation and metastasis. In vivo, MKK4DN (dominant-negative MAP2K4) expression enhanced tumor growth and lung metastasis, accompanied by decreased phospho-JNK/p53 and increased FRA1. Pan-cancer analysis revealed that MAP3K1/MAP2K4 mutations compensate for TP53 loss in regulating FOSL1 expression, particularly in tumors with moderate TP53 mutation rates.

Conclusions: Our findings establish MAP3K1 and MAP2K4 as key tumor suppressors in BRCA that operate via the JNK2-p53-FOSL1 axis. Their inactivation provides an alternative mechanism for p53 pathway disruption, adhering to the "minimal necessary alteration" principle in cancer signaling. This study highlights the dual regulatory mechanisms controlling FRA1 expression and offers insights into breast cancer heterogeneity, with potential implications for targeted therapy and patient stratification.

Background: Molecular breast imaging (MBI) has shown utility as a supplement to mammography in women with dense breasts. Background parenchymal uptake (BPU), which describes the level of Tc-99 m sestamibi in fibroglandular tissue on MBI, varies among women with similar density. Higher BPU is associated with greater breast cancer risk. The goal of this work is to investigate the histological correlations of BPU that may explain this association with risk.

Methods: In healthy women with dense tissue on mammography, we prospectively biopsied regions of fibroglandular tissue exhibiting one of the extreme categories of BPU on MBI: either photopenic or marked. Tissue composition of specimens was assessed by measuring area of epithelium, stroma, and fat and counting lobules. Lobular involution status was assessed by an expert pathologist as either none, partial, or complete. Ki-67 index and estrogen receptor-alpha expression were also assessed. Histologic features of photopenic and marked specimens were compared.

Results: Biopsies were performed in 48 women (mean age 54.9 years [SD 11.1 years]), including 20 with marked BPU and 28 with photopenic BPU. Women with marked BPU were younger (mean age 49.9 vs. 58.4 years, p = 0.004), had higher body mass index (p = 0.01), and were more likely premenopausal (p = 0.005). Marked BPU specimens had a higher proportion of epithelium (14.5% vs. 2.2%, p < 0.001), lower stromal content (44.8% vs. 84.2%, p = 0.005), similar fat (18.9% vs. 12.9%, p = 0.41), and greater lobule counts (15.5 vs. 6.3, p < 0.001) compared to photopenic specimens. Complete lobular involution was less frequent in marked tissue than in photopenic tissue (10.5% vs. 76%, p < 0.001). Ki-67 index was higher in marked BPU tissues (5.4% vs. 1.6%, p = 0.006), though the difference was attenuated after adjustment for epithelial area (p = 0.26). Estrogen receptor-alpha expression did not differ between marked and photopenic groups (25.6% vs. 28.4%, p = 0.12).

Conclusions: Marked BPU on MBI is associated with greater epithelial content, less lobular involution, and higher proliferative activity-features characteristic of tissue at elevated risk for malignant transformation. These findings suggest that BPU provides functional information beyond mammographic density, supporting its role as an imaging biomarker for breast cancer risk in women with dense breasts.

Trial registration: NCT01240278 || 11/15/2010 and NCT01588834 || 05/01/2012.