Breast Cancer Research最新文献

Background: Midkine is a heparin-binding growth factor that is overexpressed in most human malignancies, including breast cancer. While elevated midkine levels have been associated with tumor progression and aging, its role as a predictive biomarker for breast cancer risk in healthy individuals remains unclear. We previously showed that higher midkine expression in estrogen receptor-positive (ER +) breast cancer in younger (< 55) women is associated with shorter disease-free survival. We investigated whether serum midkine levels in premenopausal women are associated with subsequent risk of ER + breast cancer.

Methods: We conducted a prospective, nested case-control study within the New York University Women's Health Study (NYUWHS). Serum midkine levels were measured in baseline blood samples from 249 premenopausal women who developed ER + breast cancer more than 10 years after blood collection and 249 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) across quartiles and continuous midkine levels, adjusting for key breast cancer risk factors.

Results: Higher circulating midkine levels were associated with a marginally statistically significant lower risk of ER + breast cancer. Compared to the lowest quartile, women in the highest quartile had an OR of 0.55 (95% CI: 0.30-0.99; P for trend = 0.10). A doubling in midkine was associated with a 34% reduction in risk (OR = 0.66; 95% CI: 0.42-1.02). The inverse association was generally consistent across subgroups.

Conclusion: These findings suggest that higher baseline serum midkine levels in premenopausal women are associated with a reduced long-term risk of ER + breast cancer. This challenges prior assumptions about midkine's uniformly pro-tumorigenic role and suggests it may be a context-dependent biomarker in breast cancer development.

Background: Secondary lymphedema is characterized by limb swelling following lymphatic disruption. This results in decreased lymph flow through the collecting ducts and dermal backflow in the subdermal lymphatics. The role of dermal lymphatics in the development of lymphedema is poorly understood. The purpose of this study is to evaluate the effect of dermal lymphatic preservation in the development of lymphedema in a murine tail experimental model.

Methods: A standard murine lymphedema tail model was used as the study control. A 3 mm circumferential excision was performed 20 mm from the base of the tail. Both collecting lymphatics adjacent to the veins were transected (Full Dermal Disruption (FDD), control, n = 6). The experimental group was a modification of the standard model consisting of two hemi circumferential skin excision and collecting lymphatics transection with 3 mm interval (Partial Dermal Disruption (PDD), experimental, n = 8) maintaining continuity of capillary lymphatics. Tail volume measurements, lymphatic clearance with near Infrared Indocyanine Green (ICG) laser lymphangiography, and histology were assessed.

Results: The PDD group had lower tail volumes compared to FDD till day 28 (p < 0.001). ICG lymphangiography demonstrated better lymphatic clearance in the PDD when compared to FDD (p < 0.001). Reduced dermal thickness (p = 0.004) and collagen deposition (p = 0.008) were observed in PDD. Podoplanin-positive lymphatic vessel density was higher in PDD at the unadjusted level (p = 0.014) but did not meet Bonferroni-corrected significance (α = 0.010).

Conclusion: This study demonstrates dermal lymphatics can preserve lymphatic function despite injury to transporting lymphatic channels. Dermal lymphatics may have the potential for lymphedema prevention at the lymphatic injury site.

Background: Inflammatory breast cancer (IBC) is a rare but aggressive subtype of breast cancer characterized by rapid progression and poor prognosis. Despite its distinct clinical presentation and molecular features, the immune landscape of IBC and its potential role in driving the aggressive phenotype remain poorly understood. This study aimed to characterize the spatial immune landscape of IBC, compare it with that of subtype-matched non-inflammatory breast cancer (nIBC), and evaluate the prognostic implications of immune cell composition and localization.

Methods: We analyzed pre-treatment tumor samples from 161 IBC and 115 subtype-matched nIBC patients using immunohistochemistry (IHC) for CD8, FOXP3, CD79α, CD163, and PD-L1. Digital image analysis quantified the immune cell density and relative marker area in the tumor area (TA) and invasive margin (IM). Associations with clinicopathological features, pathological response to neoadjuvant chemotherapy (NACT), and survival were assessed using multivariate logistic regression and Cox proportional hazards models. Transcriptomic validation was performed using Affymetrix gene expression data and consensus TME deconvolution.

Results: IBC showed higher infiltration of CD163 + tumor-associated macrophages (TAMs) compared to nIBC. Gene expression data confirmed IHC findings, and pathway analysis linked high TAM density with inflammatory and proliferative pathways. The spatial distribution of immune cells was prognostically relevant, with high CD8 + T-cell infiltration (OR: 0.41, 95% CI: 0.22-0.76, P = 0.004) and low CD79α + B-cell infiltration (OR: 3.19, 95% CI: 1.68-6.03, P < 0.001) correlating with improved overall survival in IBC. Furthermore, the ratio of CD8+ T-cells to FOXP3+ regulatory T-cells within the TA was a significant prognostic indicator (OR: 0.34, 95% CI: 0.14-0.83, P = 0.018), whereas the absolute densities of either CD8+ or FOXP3 + T-cells alone were not associated with outcome.

Conclusions: These results highlight the immunosuppressive nature of the IBC microenvironment and the role of TAMs in promoting an aggressive IBC phenotype. Spatial context and the balance between the immune cells, rather than the overall abundance, was critical in determining outcome. Our findings underscore the importance of considering immune cell localization in prognostic assessment and support further investigation of TAM-targeted therapies in IBC.

Background: Basic helix-loop-helix family, member e22 (BHLHE22), a basic helix loop helix transcription factor family member, functions vary in different types of cancer. Currently, its function in triple-negative breast cancer (TNBC) is unclear.

Methods: The GSE45827 and GSE113865 datasets were used to screen potential TNBC marker. Biological websites were used to analyze BHLHE22 expression in TNBC, its relationship with the prognosis of patients with TNBC, and its potential function. A series of in vitro and in vivo experiments was performed to investigate the function of BHLHE22 in TNBC. The regulatory relationship between OTU domain-containing protein 3 (OTUD3) and BHLHE22 was verified by Co-Immunoprecipitation, ubiquitination assay, and site-specific mutation experiments. The mRNA-seq analysis was performed to identify potential genes for the anti-cancer role of BHLHE22. The transcriptional regulation of DNA replication factor 1 (CDT1) by BHLHE22 was confirmed by dual luciferase reporter assay.

Results: We identified the downregulation of BHLHE22 in TNBC tissues based on the GSE45827 and GSE113865 datasets. The expression of BHLHE22 in TBNC patients was lower than that in non-TNBC patients, and patients at stages 3 and 4 tended to express lower BHLHE22 expression than patients at stages 1 and 2. Patients with high expression of BHLHE22 had better survival prognosis than those with BHLHE22 low expression. Functional studies revealed that BHLHE22 overexpression impaired cell growth in vitro and in vivo. However, BHLHE22 silencing enhanced the malignant behaviors of cancer cells. OTUD3, a deubiquitinase known to suppress TNBC progression, was found to increase the stability of BHLHE22 protein through deubiquitination regulation. The C76 site mutation of OTUD3 eliminated the catalytic activity of OTUD3 and failed to regulate the protein stability of BHLHE22. Furthermore, BHLHE22 medicated the antitumor effect of OTUD3 in TNBC. The mRNA-seq analysis identified potential genes for the anti-cancer role of BHLHE22, involving CDT1. BHLHE22 was proved to reduce CDT1 RNA expression by blocking CDT1 transcription. The anti-proliferative effect of BHLHE22 overexpression was reversed by CDT1 overexpression.

Conclusions: Our observations demonstrate that BHLHE22 may be a promising target for TNBC therapy.