Breast Cancer Research最新文献

Background: Reproductive factors are key breast cancer risk factors, yet contemporary generational patterns remain unclear. We aimed to evaluate trends in reproductive factors among US women born between 1910 and 2000.

Methods: We conducted a serial, cross-sectional analysis of reproductive factors using data from the US National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2020. Female participants were grouped by birth cohorts (1910-1930, then by 10-year to 2000). Self-reported data were used to derive age at menarche, prevalence of age at menarche < 12 years, age at natural menopausal, prevalence of first live birth after age 30, and lifetime number of live births.

Results: Data on 28,481 US women were analyzed. From birth cohort 1910-1930 to 1990-2000, the mean age at menarche declined from 13.0 (95%CI 12.9 to 13.1) to 12.4 (95%CI 12.3 to 12.5) years (difference = - 0.6, 95%CI - 0.7 to - 0.5, p for trend < 0.001). This decline was observed in both US (12.9 [95%CI 12.9 to 13.0] to 12.4 [95%CI 12.3 to 12.5]) and non-US born (13.3 [95%CI 13.1 to 13.6] to 12.3 [95%CI 12.1 to 12.5]) women. From birth cohort 1910-1930 to 1990-2000, the prevalence of age at menarche < 12 years increased from 14.2% (95%CI 12.4 to 16.1) to 26.5% (95%CI 24.3 to 28.9%). The prevalence of first live birth after age 30 increased from 4.7% (95%CI 3.1 to 6.9%) to 10.6% (95%CI 7.3 to 15.0%) from birth cohort 1910-1930 to 1980-1990. Among women who attained menopause (up to birth cohort 1950-1960), no significant changes were observed for age at natural menopausal. However, the average lifetime number of live births declined from 3.5 to 2.4 with a significant decline in the proportion of grand multiparous women.

Conclusions: Over the past century, women in the US are attaining menarche earlier, more likely to have their first birth after age 30 and having fewer births. Parsing the extent to which changes in reproductive factors are contributing to the rising incidence of estrogen receptor positive breast cancer, especially in premenopausal women, is necessary to devise long-lasting and sustainable preventive strategies.

Background: Ductal carcinoma in situ (DCIS) is a non-invasive precursor to breast cancer that increases lifetime risk for invasive disease and, in rare cases, causes distant metastases without local recurrence. Tumor-derived small extracellular vesicles (sEVs), or exosomes, mediate tumor progression, systemic signaling, and metastasis; however, the timing of release and biodistribution of sEVs from early preinvasive lesions remains unclear.

Methods: Here, we investigated the release kinetics and systemic dissemination of sEVs secreted by DCIS cells confined to the mammary ducts using an orthotopic mouse mammary intraductal xenograft model with MCF10DCIS cells engineered to express NanoLuc (NLuc)-tagged CD63, an sEV marker. Tumor growth was monitored using bioluminescent imaging (BLI) in vivo and ex vivo; DCIS outgrowth and focal invasion were confirmed by fluorescent immunohistochemistry; and NLuc activity was assayed in tissue lysates. Next-generation RNA sequencing of brain tissue was used to evaluate gene expression changes at 28 days post-implantation (dpi).

Results: Longitudinal BLI revealed CD63-NLuc signals in mammary glands (P < 0.05), and distant organs, including spleen (P < 0.05), liver (P < 0.05), lungs (P < 0.01) and brain (P < 0.01) by day 14 followed by detection in heart tissue (P < 0.001) and in the circulation by day 21, preceding histological evidence of invasion. Further, CD63-NLuc activity was significantly and positively correlated with BLI levels in mammary glands and plasma (P < 0.05). Immune, metabolic, and stress response pathways were downregulated in brain tissue at 28 dpi compared to 3 dpi.

Conclusions: These findings demonstrate systemic dissemination of tumor-derived sEVs during DCIS progression, suggesting roles in early microenvironmental conditioning and metastatic preconditioning prior to overt invasion.

Background: Immune checkpoint blockade (ICB) therapies for triple negative breast cancer (TNBC) have yielded limited clinical benefits, which may be attributed to the immunosuppressive tumor immune microenvironment (TIME). Glucocorticoid receptor (GR) has long been thought to suppress immunity by acting on immune cells in the TIME, but no studies have investigated its function in TNBC immunotherapy.

Methods: To investigate the correlation between GR expression and the TIME, we integrated multi-omics data from The Cancer Genome Atlas (TCGA) program, Gene Expression Omnibus (GEO) database, and clinical patient cohorts. Functional validation was performed using an immunocompetent orthotopic murine TNBC model to assess the biological role of GR in tumor progression and immune regulation. Mechanistically, dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) were employed to dissect the transcriptional regulatory mechanisms of GR.

Results: Integrated analysis of TCGA and GEO datasets demonstrated a significant inverse association between GR expression and antitumor immunity in TNBC, characterized by diminished CD8 + T cell infiltration, upregulated PD-L1 expression, and reduced MHC-I presentation. In an immunocompetent orthotopic TNBC model, pharmacological GR inhibition enhanced endogenous tumor immune clearance and potentiated ICB therapy responsiveness. Mechanistic studies revealed GR's dual transcriptional regulation: dual-luciferase reporter and ChIP assays confirmed direct GR binding to the PD-L1 promoter to activate its transcription, while concurrently repressing MHC-I expression via promoter occupancy.

Conclusion: Our study identifies GR signaling as a tumor-intrinsic immunosuppressive axis in TNBC, transcriptionally activating PD-L1 while repressing MHC-I to drive immune escape. These findings propose GR-targeted therapy combined with immunotherapy as a clinically actionable strategy to reverse immune evasion.

Background: Trastuzumab, combined with chemotherapy, is the current standard treatment for both metastatic and early-stage HER2-positive (HER2 +) breast cancer. One of the mechanisms of action of trastuzumab is antibody-dependent cellular cytotoxicity (ADCC), which involves engaging FcγRIIIA (CD16) on natural killer (NK) cells. A competent immune system and properly functioning NK cells are crucial for effective ADCC, as they can influence favorable clinical outcomes. Resistance to trastuzumab often develops after about one year. We previously reported that elevated levels of miR-19a-3p in the serum of patients with metastatic HER2 + breast cancer treated with trastuzumab were associated with a favorable prognosis. Here, we aim to identify the mechanism and the immune cells responsible for elevated serum levels of miR-19a-3p.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy individuals were used to isolate naïve CD4 + T cells and NK cells. Naïve CD4 + T cells were polarized into CD4 + Th1 and CD4 + Th2 cells. NK cells were utilized for the ADCC assay. Levels of transcription factors, cytokines, and miR-19a-3p were measured using RT-qPCR. Surface markers and cytokines were analyzed by flow cytometry to characterize immune cell phenotypes.

Results: In vitro NK cell-mediated ADCC resulted in increased levels of miR-19a-3p released into the supernatants after killing breast cancer cells. In vitro polarized CD4 + Th1 cells expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. Over a long-term in vitro culture (24 days), anti-CD3/CD28 restimulation sustained higher levels of miR-19a-3p in CD4 + Th1 cells compared to CD4 + Th2 cells and their respective supernatants. CD4 + Th1 cells developed a central memory T (T_CM) phenotype (CD45RO + CCR7 + CD62L +) and expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. In patients with HER2 + metastatic breast cancer, those with elevated serum levels of miR-19a-3p and a favorable prognosis had a larger percentage of circulating activated T cells and NK cells in their blood compared to patients with lower serum levels of miR-19a-3p and a poor prognosis. The small cohort (n = 15) limits the statistical power of our retrospective study.

Discussion: Our findings suggest that elevated levels of miR-19a-3p in the serum of patients with HER2 + metastatic breast cancer may result from effective NK cell-mediated ADCC and activation of CD4 + Th1 cells, which could be responsible for the anti-tumor immune response associated with a favorable prognosis. Blood levels of miR-19a-3p might help identify breast cancer patients who have effective trastuzumab-induced anti-tumor immune responses.