Breast Cancer Research最新文献

Background: Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown.

Methods: Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein-coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments.

Results: Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells.

Conclusion: Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.

Autophagy, a crucial process in cancer, is closely intertwined with both tumor progression and drug resistance development. However, existing methods used to assess autophagy activity often pose invasiveness and time-related constraints, limiting their applicability in preclinical drug investigations. In this study, we developed a non-invasive autophagy detection system (NIADS-autophagy, also called G-cleave LC3B biosensor) by integrating a split-luciferase-based biosensor with an LC3B cleavage sequence, which swiftly identified classic autophagic triggers, such as Earle's Balanced Salt Solution and serum deprivation, through protease-mediated degradation pathways. The specificity of G-cleave LC3B biosensor was confirmed via CRISPR gene editing of pivotal autophagy regulator ATG4B, yielding diminished luciferase activity in MDA-MB-231 breast cancer cells. Notably, the G-cleave LC3B biosensor exhibited strong concordance with established autophagy metrics, encompassing LC3B lipidation, SQSTM1 degradation, and puncta accumulation analysis. To underscore the usage potential of the G-cleave LC3B biosensor, we discovered that resveratrol acts as a synergistic enhancer by significantly potentiating apoptosis in MDA-MB-231 cells when combined with doxorubicin treatment. Overall, the luminescence-based G-cleave LC3B biosensor presents a rapid and dependable avenue for determining autophagy activity, thereby facilitating high-throughput assessment of promising autophagy-associated anti-cancer therapies across diverse malignancies.

Substantial evidence supports that delay of surgery after breast cancer diagnosis is associated with increased mortality risk, leading to the introduction of a new Commission on Cancer quality measure for receipt of surgery within 60 days of diagnosis for non-neoadjuvant patients. Breast cancer subtype is a critical prognostic factor and determines treatment options; however, it remains unknown whether surgical delay-associated breast cancer-specific mortality (BCSM) risk differs by subtype. This retrospective cohort study aimed to assess whether the impact of delayed surgery on survival varies by subtype (hormone [HR] + /HER2 -, HR -/HER2 -, and HER2 +) in patients with loco-regional breast cancer who received surgery as their first treatment between 2010 and 2017 using the SEER-Medicare database. Exposure of this study was continuous time to surgery from diagnostic biopsy (TTS; days) in reference to TTS = 30 days. BCSM were evaluated as flexibly dependent on continuous time (days) to surgery from diagnosis (TTS) using Fine and Gray competing-risk regression models, respectively, by HR status. Inverse propensity score-weighting was adjusted for demographic, clinical, and treatment variables impacting TTS. Adjusted BCSM risk grew with increasing TTS across all subtypes; however, the pattern and extent of the association varied. HR + /HER2 - patients exhibited the most pronounced increase in BCSM risk associated with TTS, with approximately exponential growth after 42 days, with adjusted subdistribution hazard ratios (sHR) of 1.21 (95% CI: 1.06-1.37) at TTS = 60 days, 1.79 (95% CI: 1.40-2.29) at TTS = 90 days, and 2.83 (95% CI: 1.76-4.55) at TTS = 120 days. In contrast, both HER2 + and HR -/HER2 - patients showed slower, approximately linear growth in sHR, although non-significant in HR -HER2 -.

Background: The 313-variant polygenic risk score (PRS₃₁₃) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS₃₁₃ across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS₃₁₃ across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction.

Results: The mean PRS₃₁₃ differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS₃₁₃ distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment.

Conclusions: Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Background: Depression among breast cancer survivors is a significant concern affecting their long-term survivorship and quality of life. This study investigates the incidence of depression among breast cancer survivors and identifies associated risk factors.

Methods: This retrospective cohort study used data from the Korean National Health Insurance Service database and included 59,340 breast cancer patients without a history of depression who underwent surgery between January 1, 2010, and December 31, 2016. They were individually matched 1:2 by age with a general population without cancer (n = 99,834). The mean follow-up period was 6.4 ± 2.6 years. Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) were calculated considering death as a competing risk and adjusting for sociodemographic factors and comorbidities.

Results: Breast cancer survivors with a mean (standard deviation) age of 51.5 (9.2) years had a 39% increased risk of depression compared to non-cancer controls (sHR 1.39, 95% CI 1.36-1.42). During the first year post-diagnosis, breast cancer survivors across all ages exhibited a significantly elevated risk of depression, with a sHR of 3.23 (95% CI 3.08-3.37). Notably, younger survivors had a sHR of 4.51 (95% CI 4.19-4.85), and older survivors had a sHR of 2.56 (95% CI 2.42-2.71). One year post-surgery, younger survivors (age ≤ 50 years) showed a 1.16-fold increase in depression risk (sHR 1.16, 95% CI 1.11-1.20), while older survivors (age > 50 years) showed no significant change in risk, which decreased over time. Use of anthracycline, taxane, or endocrine therapy was associated with an increased depression risk (sHR 1.17, 95% CI 1.13-1.22; sHR 1.12, 95% CI 1.07-1.16; and sHR 1.27, 95% CI 1.14-1.41, respectively), with endocrine therapy showing a 41% increased depression risk in older survivors (sHR 1.41, 95% CI 1.23-1.61).

Conclusion: This study demonstrates a significant association between breast cancer and depression, with a particularly heightened risk in younger survivors within the first year post-diagnosis. Special attention is needed to meticulously screen for depressive symptoms during the early follow-up years for breast cancer survivors who are premenopausal or have undergone chemotherapy and endocrine therapy.

Background: Treatment options for triple-negative breast cancer (TNBC) are limited and patients face a poor prognosis. Here, we sought to identify drugs that target TNBC vulnerabilities and understand the biology underlying these responses. We analyzed the Broad Institute DepMap to identify recurrent TNBC vulnerabilities and performed a 45-compound screen on vulnerability-related pathways on a set of up to 8 TNBC cell lines. We identified a subset of cell lines with an ITGAV vulnerability and a differential sensitivity to cilengitide, an integrin inhibitor targeting ITGAV:ITGB3 and ITGAV:ITGB5. Next, we sought to understand cilengitide resistance and response biomarkers. Clinical trials targeting integrins continue enrolling patients, necessitating an understanding of how these drugs affect tumors.

Methods: We combined in vitro assays with computational approaches to systematically explore the differential sensitivity to cilengitide and resistance mechanisms. We tested an additional pan-ITGAV inhibitor (GLPG0187) to determine how generalizable our findings on cilengitide sensitivity might be to integrin inhibition. ITGB4, ITGA3, and ITGA6 knockdown experiments assessed the importance of integrin monomers in cell attachment during cilengitide treatment. Additionally, we explored the role of extracellular matrix (ECM) proteins in cilengitide response by performing cell replating experiments and by culturing on collagen, fibronectin, or laminin coated plates.

Results: We discovered that cell-derived ECM modulates cilengitide sensitivity and exogenous fibronectin addition conferred resistance to all sensitive TNBC cell lines, though fibronectin expression did not correlate with sensitivity. Instead, elevated overall integrin protein levels, not specific integrins, in TNBC cells positively correlated with resistance. This suggested that high pan-integrin expression promotes cilengitide resistance. Thus, we tested cilengitide in six luminal breast cancer cell lines (which have low integrin levels); all were sensitive. Also, pan-ITGAV inhibitor, GLPG0187, showed the same sensitivity profile across our TNBC cell lines, suggesting our findings apply to other integrin inhibitors.

Conclusions: Integrin inhibitors are appealing candidates to pursue as anti-cancer drugs because they are generally well-tolerated, but their efficacy is mixed, possibly due to the absence of predictive markers. Cilengitide induces death in breast cancer cells with low integrin abundance, where complementary ECM promotes survival. Thus, integrin inhibition in breast cancer warrants further study.

Background: Human mammary epithelial cell (HMEC) cultures encounter a stress-associated barrier termed stasis, during which most cells adopt a senescence-like phenotype. From these cultures, rare variants emerge from the basal epithelial population, re-initiating growth. Variants exhibit pre-malignant properties, including an aberrant epigenetic program that enables continued proliferation and acquisition of genetic changes. Following oncogenic transformation, variants produce tumors that recapitulate the histopathological characteristics of metaplastic breast cancer (MBC), a rare and aggressive subtype marked by the differentiation of neoplastic epithelium into squamous and mesenchymal elements.

Methods: Using a serum-free HMEC culture system, we probed the capacity for phenotypic plasticity inherent to basal epithelial cell populations from human breast tissue as they navigated stasis and emerged as variant populations.

Results: We observed robust activation of a TGF-β-dependent epithelial-mesenchymal transition (EMT) program in basal epithelial cells during stasis, followed by subsequent attenuation of this program in emerging variants. Inhibition of the TGF-β pathway or depleting the EMT regulators Snail or Slug allowed basal epithelial cells to collectively bypass stasis, demonstrating that cellular dysfunction and arrest resulting from TGF-β and EMT activation are central to this in vitro barrier. The spontaneous emergence of variants from stasis cultures was associated with a restricted EMT trajectory, characterized by the stabilization of hybrid EMT states associated with greater proliferative capacity, rather than progressing to a complete mesenchymal state characterized by irreversible growth arrest. Epigenetic mechanisms, which contributed to the dysregulated growth control characteristic of the variant phenotype, also contributed to the stability of the hybrid EMT program in variants. By overcoming the cellular dysfunction and growth arrest resulting from TGF-β and complete EMT, variants exhibited a higher oncogenic transformation efficiency compared to pre-stasis basal epithelial cells. Inhibiting the TGF-β pathway prior to stasis significantly reduced EMT in the basal epithelial population, alleviated selective pressure driving variant emergence, and also enhanced oncogenic transformation efficiency, resulting in tumors with markedly diminished metaplastic differentiation.

Conclusions: This study reveals how an epigenetic program governs basal epithelial cell fate decisions and contributes to the development of MBC progenitors by restricting access to terminal mesenchymal states that induce growth arrest and, instead, favoring hybrid EMT states with enhanced tumorigenic potential.

Background: The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data on HOXB13 expression in HER2+ and ER- breast cancers. Herein, we studied the expression of HOXB13 in large cohorts of HER2+ and ER- breast cancers.

Methods: We investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescence in situ hybridization.

Results: In the TCGA breast cancer cohort, HOXB13 gene expression was significantly higher in HER2+ versus HER2- breast cancers, and its expression was also significantly higher in the ER- versus ER+ breast cancers. HOXB13 is frequently co-gained or co-amplified with ERBB2. Joint copy gains of HOXB13 and ERBB2 occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial loss that includes the tumor suppressor BRCA1. ERBB2/HOXB13 co-amp tumors with interstitial BRCA1 loss exhibit a mutational signature associated with APOBEC deaminase activity and copy number signatures associated with chromothripsis and genomic instability. Among ERBB2-amplified tumors of different tissue origins, ERBB2/HOXB13 co-amp with a BRCA1 loss appeared to be enriched in breast cancer compared to other tumor types. Lastly, patients with ERBB2/HOXB13 co-amplified and BRCA1 lost tumors displayed a significantly shorter progression-free survival (PFS) than those with ERBB2-only amplifications. The difference in PFS was restricted to the ER- subset patients and this difference in PFS was not solely driven by HOXB13 gene expression.

Conclusions: HOXB13 is frequently co-gained with ERBB2 at both low-copy number level or as complex high-level amplification with relative BRCA1 loss. ERBB2/HOXB13 amplified, BRCA1-lost tumors are strongly enriched in breast cancer, and patients with such breast tumors experience a shortened PFS.

Background: Intraoperative radiotherapy (IORT) is a convenient treatment techniques for patients with early-stage breast cancer. We aimed to compare the outcome of IORT to that of whole-breast external beam radiotherapy (EBRT) in highly selected breast cancer patients based on the 2023 American Society for Radiation Oncology (ASTRO) Clinical Practice Guideline for Partial Breast Irradiation (PBI).

Patients and methods: We reviewed patients who underwent breast-conserving surgery (BCS) and received either IORT or EBRT for early-stage breast cancer between 2014 and 2019. The outcomes of these patients were analyzed and compared across different risk stratifications according to the 2023 ASTRO Clinical Practice Guideline for PBI, which categorized the patients into "recommended", "conditionally recommended", or "conditionally not recommended" groups.

Results: A total of 732 patients were enrolled with a mean follow-up time of 5.1 years. Among patients in the recommended group, the locoregional recurrence rates were 2.0% for IORT and 2.3% for EBRT (p = 0.978). Conversely, in the conditionally recommended or conditionally not recommended groups, IORT exhibited significantly higher locoregional recurrence rates compared to EBRT: in the conditionally recommended group, IORT had a recurrence rate of 11.1% versus 3.0% for EBRT (p = 0.044), and in the conditionally not recommended group, IORT had a rate of 13.8% versus 2.5% for EBRT (p = 0.010).

Conclusions: The locoregional recurrence rate in the IORT group was comparable to that of the EBRT group for patients recommended for PBI. However, for patients categorized as conditionally recommended or conditionally not recommended for PBI, the IORT group showed a higher locoregional recurrence rate, highlighting the need for careful patient selection.