Explore the vast range of titles available.

Background The primary cilium is a microtubule-based and nonmotile organelle functioning as a cellular antenna that is involved in the regulation of cell proliferation, differentiation, and migration. In breast cancer cells, the primary cilium is a structure that decreases in incidence with increasing degrees of transformation and may be biologically more important in estrogen receptor (ERα)-negative breast cancer cells. Split ends (SPEN) is an ERα corepressor that we have identified as a tumor suppressor protein in ERα-positive breast cancer cells whose hormone-independent roles in breast cancer have never been explored. Methods We determined the hormone-independent transcriptional program regulated by the ERα cofactor SPEN in breast cancer using DNA microarrays. The biological functions regulated by SPEN independently of hormones were studied in vitro in ERα-positive and ERα-negative breast cancer cells. Finally, we examined the clinical relevance of SPEN expression in cohorts of breast cancer samples with outcome data. Results We found that SPEN is coexpressed with a number of genes involved in ciliary biology, including the ciliogenic transcription factor RFX3, in a hormone-independent manner. SPEN reexpression in T47D cells containing a nonsense mutation in SPEN restored the primary cilium, whereas its knockdown in MCF10A and Hs578T cells considerably decreased primary cilia levels. We also report that SPEN regulates migration in breast cells, but only in those harboring primary cilia, and that KIF3A silencing, a critical factor in primary cilia, partially reverses SPEN’s effects, suggesting that SPEN may coordinate cellular movement through primary cilia-dependent mechanisms. Finally, we found that high SPEN RNA levels were predictive of early metastasis in two independent cohorts of 77 (HR 2.25, P  = 0.03) and 170 (HR = 2.23, P  = 0.004) patients with ERα-negative breast cancer. Conclusions Together, our data demonstrate a role for SPEN in the regulation of primary cilia formation and cell migration in breast cancer cells, which may collectively explain why its expression is associated with time to metastasis in cohorts of patients with ERα-negative breast cancers.

Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited. Histone modifications in cancer can contribute to pathogenesis. Here, the authors demonstrate that targeting epigenetic modifier Ezh2 hinders metastatic behaviour in Luminal B breast cancer models, and highlight a mechanism where Ezh2 contributes to metastatic behaviour by repression of FOXC1.

Background Cancer cells cooperate with cells that compose their environment to promote tumor growth and invasion. Among them, adipocytes provide lipids used as a source of energy by cancer cells and adipokines that contribute to tumor expansion. Mechanisms supporting the dynamic interactions between cancer cells and stromal adipocytes, however, remain unclear. Methods We set-up a co-culture model with breast cancer cells grown in 3D as mammospheres and human adipocytes to accurately recapitulate intrinsic features of tumors, such as hypoxia and cancer cell–adipocytes interactions. Results Herein, we observed that the lipid droplets’ size was reduced in adipocytes adjacent to the mammospheres, mimicking adipocyte morphology on histological sections. We showed that the uncoupling protein UCP1 was expressed in adipocytes close to tumor cells on breast cancer histological sections as well as in adipocytes in contact with the mammospheres. Mammospheres produced adrenomedullin (ADM), a multifactorial hypoxia-inducible peptide while ADM receptors were detected in adipocytes. Stimulation of adipocytes with ADM promoted UCP1 expression and increased HSL phosphorylation, which activated lipolysis. Invalidation of ADM in breast cancer cells dramatically reduced UCP1 expression in adipocytes. Conclusions Breast tumor cells secreted ADM that modified cancer–associated adipocytes through paracrine signaling, leading to metabolic changes and delipidation. Hence, ADM appears to be crucial in controlling the interactions between cancer cells and adipocytes and represents an excellent target to hinder them.

Background Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and carries a worse prognosis relative to other breast cancer subtypes. This systematic review and meta-analysis evaluated the prognostic value of circulating tumor DNA (ctDNA) in early-stage TNBC. Methods A literature search was conducted using Ovid Medline, Elsevier EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science Databases for publications up to 11/16/2023. Results were uploaded to Covidence and assessed by two independent reviewers. Studies assessing the use of ctDNA to predict recurrence free survival and related outcomes as well as overall survival were included. All recurrence outcomes were combined during analysis. Statistical analysis was performed using Revman Web. Log-hazard ratios (HR) were pooled for studies reporting recurrence and death as a time-to-event outcomes. Odds ratios (OR) were calculated and pooled for studies reporting patient-level data on recurrence, death, and pathological complete response (pCR). Prospero ID: CRD42023492529. Results A total of 3,526 publications were identified through our literature search, and 20 publications ( n  = 1202 patients) were included in the meta-analysis. In studies that reported recurrence as a time-to-event outcome, post-neoadjuvant (before or after surgery) ctDNA + status was associated with a higher likelihood of disease recurrence (HR 4.12, 95% confidence interval [CI] 2.81–6.04). For studies that reported patient-level data, post-neoadjuvant ctDNA + status was associated with higher odds of disease recurrence (OR 6.72, 95% CI 3.61–12.54). Pooled log-HR also revealed that ctDNA + status in the post-neoadjuvant setting (before or after surgery) was associated with worse overall survival (HR 3.26, 95% CI 1.88–5.63). Conclusions Our findings suggest that ctDNA could be used as a prognostic biomarker to anticipate the risk of relapse. However, it remains unclear if therapeutic intervention for patients who are ctDNA + can improve outcomes. While more studies are needed before incorporating ctDNA into clinical practice, the findings of this meta-analysis are reassuring and show the promise of ctDNA as a biomarker.

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21 CIP1 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy. The HER2 monoclonal antibody, Trastuzumab, is the current standard treatment for HER2+ cancers but resistance to therapy occurs. Here, the authors show that activation of the PKR/eIF2α-P pathway exhibits anti-tumor effects in HER2+ cancer and is required for the response to Trastuzumab.

With current advances in neoadjuvant systemic therapy (NST) and improved breast imaging, the potential of nonoperative therapy for invasive breast cancer has emerged as a viable option when utilizing meticulous image-guided percutaneous biopsy to document pathologic complete response. Feasibility clinical trials utilizing this approach are being performed by teams of investigators from single and multicenter/cooperative groups around the world. Imaging alone after NST lacks sufficient sensitivity and specificity in predicting pCR and therefore cannot be utilized for clinical selection of patients for omission of surgery. Imaging with adequate sampling after NST of the residual lesions (or around the remaining clip if a complete radiologic response occurs) appears to be essential in selecting patients with pCR to lower the false-negative rates based on initial reported feasibility studies to identify pCR without surgery that range from 5 to 49%. In this manuscript, recently completed, ongoing, and planned clinical feasibility trials and a new omission of surgery trial are described. Drastic rethinking of all diagnostic and therapeutic management strategies that are ordinarily utilized for patients who receive standard breast cancer surgery is required. A roadmap of essential questions and issues that will have to be resolved as the field of nonoperative breast cancer management advances is described in detail.

Blood sample processing and handling can have a significant impact on the stability and levels of proteins measured in biomarker studies. Such pre-analytical variability needs to be well understood in the context of the different proteomics platforms available for biomarker discovery and validation. In the present study we evaluated different types of blood collection tubes including the BD P100 tube containing protease inhibitors as well as CTAD tubes, which prevent platelet activation. We studied the effect of different processing protocols as well as delays in tube processing on the levels of 55 mid and high abundance plasma proteins using novel multiple-reaction monitoring-mass spectrometry (MRM-MS) assays as well as 27 low abundance cytokines using a commercially available multiplexed bead-based immunoassay. The use of P100 tubes containing protease inhibitors only conferred proteolytic protection for 4 cytokines and only one MRM-MS-measured peptide. Mid and high abundance proteins measured by MRM are highly stable in plasma left unprocessed for up to six hours although platelet activation can also impact the levels of these proteins. The levels of cytokines were elevated when tubes were centrifuged at cold temperature, while low levels were detected when samples were collected in CTAD tubes. Delays in centrifugation also had an impact on the levels of cytokines measured depending on the type of collection tube used. Our findings can help in the development of guidelines for blood collection and processing for proteomic biomarker studies.

The chemokine receptor CXCR4 is an important factor in the migration, invasiveness, metastasis and proliferation of breast cancer cells. We have retrospectively analyzed the levels of expression of CXCR4 in a large cohort of breast cancers and pre-invasive breast samples linked to clinical data. A total of 1808 invasive breast carcinomas and 214 pre-invasive breast samples could be analyzed in correlation with basic clinico-pathological data such as hormone receptor status, HER2 status and tumor grade. The majority of breast cancers expressed either nuclear or cytoplasmic staining or both. CXCR4 cytoplasmic expression was associated with parameters of tumor aggressivity (tumor grade and lymph node status) and had prognostic value (age-adjusted hazard ratio=1.73; Confidence Interval: 1.07-2.77) with respect to disease-specific survival. CXCR4 positivity in the cytoplasm but not the nucleus was associated with HER2 expression and amplification as well as with hormone receptor negativity (both ER and PR). The percentage of nuclear staining increased from normal breast tissue (20%) to ductal carcinoma-in-situ DCIS (43%) to invasive cancer (67%) while CXCR4 was expressed in the cytoplasm of 67% of (DCIS) cases (double that in normal breast samples), suggesting an important role in breast tumor progression. The CXCR4 receptor is expressed in many breast cancers, justifying its development as a therapeutic target in breast cancer patients. Its cytoplasmic expression is associated with breast tumor progression, suggesting potential value as a diagnostic marker.

Background Chromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers. However, the mere assessment of the extent of genomic changes, amplifications and deletions may reduce the complexity of genomic data observed by array comparative genomic hybridization (array CGH). We present here a novel approach to array CGH data analysis, which focuses on putative breakpoints responsible for rearrangements within the genome. Results We performed array comparative genomic hybridization in 29 primary tumors from high risk patients with breast cancer. The specimens were flow sorted according to ploidy to increase tumor cell purity prior to array CGH. We describe the number of chromosomal breaks as well as the patterns of breaks on individual chromosomes in each tumor. There were differences in chromosomal breakage patterns between the 3 clinical subtypes of breast cancers, although the highest density of breaks occurred at chromosome 17 in all subtypes, suggesting a particular proclivity of this chromosome for breaks. We also observed chromothripsis affecting various chromosomes in 41% of high risk breast cancers. Conclusions Our results provide a new insight into the genomic complexity of breast cancer. Genomic instability dependent on chromosomal breakage events is not stochastic, targeting some chromosomes clearly more than others. We report a much higher percentage of chromothripsis than described previously in other cancers and this suggests that massive genomic rearrangements occurring in a single catastrophic event may shape many breast cancer genomes.

Purpose While enhanced breast screening of germline pathogenic variant (GPV) carriers results in earlier stage at diagnosis, the impact of tumour biology and GPV on chemotherapy receipt in early-stage disease remains understudied. Methods We retrospectively reviewed treatment administered following a first diagnosis of BRCA1/2 - and PALB2 -associated breast cancer between 2002 and 2022. Chemotherapy receipt was compared according to tumor size, biologic subtype, and GPV. Subgroup analyses were performed in women with T1N0 disease and in those with pre-diagnostic awareness of their GPV. Results Overall, 309 affected BRCA1/2 and PALB2 carriers with a median age of 43 years at breast cancer diagnosis (range, 19–80 years) were included; 160 (51.8%) BRCA1 , 130 (42.1%) BRCA2 , and 19 (6.1%) PALB2 carriers. Chemotherapy was administered in 70.9% of index breast cancer cases and was significantly associated with younger age, tumor size, histologic grade, nodal status, and biologic subtype (all p  < 0.05). Chemotherapy receipt was 80.6% in BRCA1 -associated breast cancers compared to 56.9% in BRCA2 and 84.2% in PALB2 associated breast cancers ( p  < 0.001). In subgroup analysis of early stage, T1N0 disease, chemotherapy was administered in 78.9% BRCA1 and 59.5% BRCA2/PALB2 patients ( p  = 0.04). Pre-diagnostic awareness of a GPV in BRCA1/2 or PALB2 was associated with smaller invasive tumors (%T1, 50% vs. 32.9%; p  = 0.002) and node-negative invasive disease (87.1% vs. 72.2%), as well as a reduced likelihood of chemotherapy (59.7% vs. 74.3%, p  = 0.02). Conclusion Chemotherapy receipt is high in BRCA1/2 and PALB2 -associated breast cancers including in early stage, node-negative disease. Pre-diagnostic awareness is associated with a lower likelihood of requiring chemotherapy for a breast cancer diagnosis.