Multiple Breast Cancer Research Articles

Evaluation of multiple breast cancer polygenic risk score panels in women of Latin American heritage.

A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European and Asian ancestry, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L specific variants among self-reported H/L women. PRS performance was evaluated using multivariable logistic regression and the area under the receiver operating characteristic curve (AUC). Both European and Asian PRSs performed worse in H/L samples compared to original reports. The best European PRS performed better than the best Asian PRS in pooled H/L samples. European PRSs had decreased performance with increasing Indigenous American (IA) ancestry while Asian PRSs had increased performance with increasing IA ancestry. The addition of 2 H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry and did not impact the performance of PRSs in individuals with lower IA ancestry. A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry specific panels, could be used in clinical practice. Results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry specific variants into PRS for clinical application.

Breast-Conserving Surgery versus Mastectomy in Patients with Multiple Breast Cancer – Changing the Paradigm in Bulgaria

Breast-Conserving Surgery versus Mastectomy in Patients with Multiple Breast Cancer – Changing the Paradigm in Bulgaria

Saprophytic fungus (Ganoderma sessile) restrained Treg recruitment in the tumor microenvironment by down-regulating CCL28/CCR10 pathway

Ganoderma sessile, a saprophytic fungus, is a traditional Chinese medicinal material used in Chinese folk medicine and cuisine for its potential to enhance cancer patients immunity in clinical practice. However, the underlying mechanisms of its therapeutic effects remain elusive. Therefore, we explored the edible value to determine the underlying mechanisms of GS through multiple breast cancer models. GS was found to suppress tumor growth and lung metastasis, and prolong survival after surgery. It significantly increased tumor-infiltrating CD44HiCD62LHiCD8+ TCM cells while decreasing CD4+CD25+CD127− Treg cells in both lymph nodes and tumors. The mechanism behind GS’s effects primarily involved modulation of the Hif1-a/CCL28 pathway associated with Treg recruitment. Furthermore, GS could reduce CCR10 levels on the surface of Tregs. Collectively, GS inhibits tumor growth and pulmonary metastasis by restraining Treg recruitment through downregulation of the CCL28/CCR10 pathway—a finding which highlights its potential as a natural anti-tumor immune agent warranting further exploration.

Causality Between Immune Cells, Metabolites and Breast Cancer: Mendelian Randomization and Mediation Analysis.

Previous studies have shown that immune cells and metabolites are associated with the development of breast cancer, but the causal relationship is unclear. We use Mendelian randomization (MR) to explore potential connections between them. Based on two sample MR studies, we evaluated the causal relationship between 731 immune cell traits, 1400 metabolites and breast cancer. In addition, we evaluated the mediating role of metabolites between immune cells and breast cancer using two-step MR Studies. Pooled GWAS data on 731 immune cell traits (n = 3757), 1400 metabolites (n = 8299) and breast cancer (ncase = 122,977, ncontrol = 105,974) were obtained from publicly available authoritative databases. We mainly used inverse variance weighted (IVW) method combined with Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods. The results of MR Studies showed that 3 immune cells and 15 metabolites were associated with an increased risk of breast cancer. 8 immune cells and 11 metabolites are associated with a reduced risk of breast cancer. Mediating MR Analysis showed that 6 metabolites, Tricosanoyl sphingomyelin (d18:1/23:0) levels(Mediated proportion:17.5%), N-palmitoyl-heptadecasphingosine (d17:1/16:0) levels(8.74%), Inosine 5'-monophosphate (IMP) to phosphate ratio(11.3%), Glutamine to asparagine ratio(5.43%), Oleoyl-linoleoyl-glycerol (18:1/18:2) [2] levels(8.48%), and Sphinganine-1-phosphate levels(8.68%), were found to mediate the relationship between immune cells and breast cancer. Our study reveals a potential causal relationship among multiple immune cells traits, metabolites, and breast cancer. It provides valuable clues and potential therapeutic targets for breast cancer biomarker discovery and breast cancer treatment.

Role function in postmenopausal women during aromatase inhibitor therapy for breast cancer.

Few studies have examined aromatase inhibitor therapy relating to role function in breast cancer survivors of working age. Our study sought to identify how pre-therapy sociodemographic and health/treatment-related characteristics, as well as patient-reported symptoms measured every six-months, influence role function during 18months of AI therapy for early-stage breast cancer. We performed a secondary analysis of longitudinal study data using linear mixed-effects modeling to examine role physical (RP) and role emotional (RE) functioning measured with the Medical Outcome Study Short Form 36 v2. The sample of postmenopausal women (N = 351) consisted of three cohorts: chemotherapy followed by anastrozole (CFAI), anastrozole only (AI only), and non-cancer controls. Our choice of variables and interpretation of findings was theoretically based on the Cancer Survivorship and Work Model. Stepwise backward deletion determined which predictors to include in the final model, accounting for treatment group. Both treatment groups were associated with greater limitations in RP functioning than controls. CFAI had twice the impact on RP compared to AI only. While the RP model displayed significant predictors across sociodemographic, health/treatment, and symptom characteristics, only symptoms were associated with greater limitations in RE functioning. Findings were significant at p < .05. Transitioning from acute to extended survivorship is a critical juncture in which multiple factors place breast cancer survivors at risk of diminished role function. Early interventions to address role function limitations during systemic treatment may lead to better work outcomes and improve the quality of long-term survivorship.

A phenocopy signature of TP53 loss predicts response to chemotherapy

In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.

Breast Surgical Conservation Therapy versus Mastectomy in Multifocal or Multicentric Breast Cancer; A Systematic Review and Meta-Analysis

Abstract Background Breast cancer affects 1.7 million women annually worldwide, the majority of whom are treated surgically. Multiple ipsilateral breast cancers are collectively defined as more than one synchronous ipsilateral cancer at diagnosis. The term Multiple ipsilateral breast cancers denotes either multifocal breast cancers that occur within proximity separated by approximate radiological distances of 20–50 mm of normal tissue, or multicentric cancers occurring further apart in the breast at distances exceeding 50 mm. Objective To assess overall survival (OS), local recurrence and cosmetic results between conservative surgical approach and mastectomy in ipsilateral MF and MC breast cancer and to explore whether BCT was feasible for female patients with MF/MC breast cancer. Patients and Methods The PubMed, web of science and Scopus were searched on November 2010. The keywords were ipsilateral multiple breast cancer, conservative surgery and Radical mastectomy. Results In our Study twelve trials included 1906 patients, six trials regarding comparison between Breast conservative surgery and mastectomy and six trials regarding Breast conservative surgery in the management of the multifocal/multicentric breast lesions. Regarding local recurrence was assessed in six trials comparing between Breast conservative surgery and mastectomy and six trials regarding Breast conservative surgery in the management of the multifocal/multicentric breast lesions. Conclusion In MF/MC breast cancer patients, Local and regional recurrence in addition to, distant metastasis in patients undergoing BCT has no statistically difference compared to patients undergoing mastectomy. Further prospective studies should be investigated to refine the prognosis and to optimize the treatment in patients with MF/MC breast cancer.

Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe)

We propose a new method for the simultaneous selection and estimation of multivariate sparse additive models with correlated errors. Our method called Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe) simultaneously selects among null, linear, and smooth non-linear effects for each predictor while incorporating joint estimation of the sparse residual structure among responses, with the motivation that accounting for inter-response correlation structure can lead to improved accuracy in variable selection and estimation efficiency. CoMPAdRe is constructed in a computationally efficient way that allows the selection and estimation of linear and non-linear covariates to be conducted in parallel across responses. Compared to single-response approaches that marginally select linear and non-linear covariate effects, we demonstrate in simulation studies that the joint multivariate modeling leads to gains in both estimation efficiency and selection accuracy, of greater magnitude in settings where signal is moderate relative to the level of noise. We apply our approach to protein-mRNA expression levels from multiple breast cancer pathways obtained from The Cancer Proteome Atlas and characterize both mRNA-protein associations and protein-protein subnetworks for each pathway. We find non-linear mRNA-protein associations for the Core Reactive, EMT, PIK-AKT, and RTK pathways. Supplementary Materials are available online.

Quality of life of women with a screen-detected versus clinically detected breast cancer in the Netherlands: a prospective cohort study.

Breast cancer (BC) screening enables early detection of BC, which may lead to improved quality of life (QoL). We aim to compare QoL between women with a screen-detected and clinically detected BC in the Netherlands. We used data from the 'Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation' (UMBRELLA) between October 2013 and March 2022. Patients were categorized as screen-detected or clinically detected. We analysed three questionnaires, namely EORTC QLQ C-30, BR23, and HADS (Hospital Anxiety and Depression Scale) completed by BC patients shortly after diagnosis (T1) and one-year after treatment (T2). Independent t-tests were performed to compare QoL average differences between the two groups. Bonferroni-corrected p-value significance threshold of 0.00057 was used. The magnitude of differences was calculated using Cohen's d. The clinical relevance of QLQ-C30 differences was assessed based on interpretation guideline of EORTC-QLQ-C30 results. After applying inclusion and exclusion criteria, there were 691 women with screen-detected BC and 480 with clinically detected BC. Generally, screen-detected BC patients reported a better QoL. At T1, their average QLQ-C30 summary score was higher (86.1) than clinically detected BC patients (83.0) (p < 0.0001). Cohen's d for all items ranged between 0.00 and 0.39. A few QLQ-C30 score differences were clinically relevant, indicating better outcomes in emotional functioning, general health, constipation, and fatigue for women with screen-detected BC. In the Netherlands, women with screen-detected BC reported statistically significant and better QoL than women with clinically detected BC. However, clinical relevance of the differences is limited.

MiRNA-driven sensitization of breast cancer cells to Doxorubicin treatment following exposure to low dose of Zinc Oxide nanoparticles

The impact of Engineered nanomaterials (ENMs) (i.e., Zinc Oxide nanoparticles (ZnO NPs)) on human health has been investigated at high and unrealistic exposure levels, overlooking the potential indirect harm of subtoxic and long exposures. Therefore, this study aimed to investigate the impacts of subtoxic concentrations of zinc oxide (ZnO NPs) on breast cancer cells’ response to Doxorubicin. Zinc oxide nanoparticles caused a concentration-dependent reduction of cell viability in multiple breast cancer cell lines. A subtoxic concentration of 1.56 µg/mL (i.e., no observed adverse effect level) was used in subsequent mechanistic studies. Molecularly, miRNA profiling revealed significant downregulation of 13 oncogenic miRNAs (OncomiRs) in cells exposed to the sub-toxic dose of ZnO NPs followed by doxorubicin treatment. Our comprehensive bioinformatic analysis has identified 617 target genes enriched in ten pathways, mainly regulating gene expression and transcription, cell cycle, and apoptotic cell death. Several tumor suppressor genes emerged as validated direct targets of the 13 OncomiRs, including TFDP2, YWHAG, SMAD2, SMAD4, CDKN1A, CDKN1B, BCL2L11, and TGIF2. This study insinuates the importance of miRNAs in regulating the responsiveness of cancer cells to chemotherapy. Our findings further indicate that being exposed to environmental ENMs, even at levels below toxicity, might still modulate cancer cells’ response to chemotherapy, which highlights the need to reestablish endpoints of ENM exposure and toxicity in cancer patients receiving chemotherapeutics.

Increasing opportunities for breast-conserving therapy in multiple ipsilateral breast cancer: Dutch nationwide study.

An increasing number of breast cancer patients undergo breast-conserving surgery (BCS), but multiple ipsilateral breast cancer (MIBC) is still considered a relative contraindication for breast conservation. This study provides an update on trends in the surgical management for MIBC over a 10-year period. Nationwide data from the Netherlands Cancer Registration of all patients diagnosed with breast cancer between 2011 and 2021 were analysed. The primary outcomes of this study were the incidence of MIBC and the trend in breast surgery type among patients between 2011 and 2021. Secondary outcomes were the positive resection margin rates in patients treated with BCS, the proportion of patients requiring re-excision and overall survival. In total, 114 433 patients (83%) with unifocal breast cancer and 23 932 patients (17%) with MIBC were identified. The incidence of MIBC was stable (17%) over the years. Overall BCS rates, both primary and after neoadjuvant chemotherapy, increased in MIBC from 29% in 2011 to 41% in 2021. Re-excision was performed in 1348 patients (n = 8455, 16%). The 5-year OS estimate for patients with MIBC treated with BCS was 93%. The pathological complete response (pCR) in MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy was 23%. The breast conservation rate in MIBC has increased over the last decade. In addition, 23% of MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy achieved a pCR. This suggests increasing opportunities for even more BCS in MIBC.

An super sensitive Multi-Modal controlled release biosensor with label- and enzyme- free assisted single step simultaneously detect multiple breast cancer biomarkers

Despite the fact that homogeneous biosensing strategies have been proven to be advantageous, it remains a difficult task to identify multiple tumor biomarkers. Our proposition entails the creation of a groundbreaking biosensor that combines electrochemical and fluorescent techniques, enabling simultaneous detect multiple biomarkers with label- and enzyme-free assistance in a single step. Porous UIO-66-NH2 nanovessels loaded with 3,3′,5,5′ −tetramethylbenzidine (TMB) and methylene blue (MB) double signal dyes, along with double-stranded DNA (dsDNA) formed by the aptamer chain of human epidermal growth factor receptor-2 (HER2) and estrogen receptor (ER) and its complementary chain as a gated switch to the envelope MOFs, were utilized to create functional MOFs (dsDNA@MB@UIO and dsDNA@TMB@UIO). When HER2 and ER targets are present, the chain replacement reaction led to the formation of a biomarker-aptamer complex, resulting in the destruction of the dsDNA structure on the surface of MOF and the liberation of MB and TMB. The concentration of the two target biomarkers determines the strength of the electrochemical and fluorescent signals produced. By combining targeted biomarkers, signal enhancement, and dual-signal detection into one unified process, the amount of test error caused by the multi-step detection needed in prior studies is significantly decreased. We executed the detect HER2 and ER, achieving detection limits of 4.7 and 5.9 fg/mL in 4.7–1000 pg/mL linear range with good selectivity, stability, reproducibility, and acceptable applicability. The proposed biosensor for developing dsDNA@MB@UIO and dsDNA@TMB@UIO is promising for the early and sensitive detection of cancer biomarkers.

Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth.

Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-β (LTβ) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTβ promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTβ activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTβ signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumours. Our findings highlight LTβ as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.

Evolutionarily conserved enhancer-associated features within the MYEOV locus suggest a regulatory role for this non-coding DNA region in cancer.

The myeloma overexpressed gene (MYEOV) has been proposed to be a proto-oncogene due to high RNA transcript levels found in multiple cancers, including myeloma, breast, lung, pancreas and esophageal cancer. The presence of an open reading frame (ORF) in humans and other primates suggests protein-coding potential. Yet, we still lack evidence of a functional MYEOV protein. It remains undetermined how MYEOV overexpression affects cancerous tissues. In this work, we show that MYEOV has likely originated and may still function as an enhancer, regulating CCND1 and LTO1. Firstly, MYEOV 3' enhancer activity was confirmed in humans using publicly available ATAC-STARR-seq data, performed on B-cell-derived GM12878 cells. We detected enhancer histone marks H3K4me1 and H3K27ac overlapping MYEOV in multiple healthy human tissues, which include B cells, liver and lung tissue. The analysis of 3D genome datasets revealed chromatin interactions between a MYEOV-3'-putative enhancer and the proto-oncogene CCND1. BLAST searches and multi-sequence alignment results showed that DNA sequence from this human enhancer element is conserved from the amphibians/amniotes divergence, with a 273bp conserved region also found in all mammals, and even in chickens, where it is consistently located near the corresponding CCND1 orthologues. Furthermore, we observed conservation of an active enhancer state in the MYEOV orthologues of four non-human primates, dogs, rats, and mice. When studying this homologous region in mice, where the ORF of MYEOV is absent, we not only observed an enhancer chromatin state but also found interactions between the mouse enhancer homolog and Ccnd1 using 3D-genome interaction data. This is similar to the interaction observed in humans and, interestingly, coincides with CTCF binding sites in both species. Taken together, this suggests that MYEOV is a primate-specific gene with a de novo ORF that originated at an evolutionarily older enhancer region. This deeply conserved putative enhancer element could regulate CCND1 in both humans and mice, opening the possibility of studying MYEOV regulatory functions in cancer using non-primate animal models.

Quality control and validation of extracellular vesicles isolated from cultured human breast cancer cells

ObjectiveExtracellular vesicles (EVs) have been shown to play a critical role in promoting tumorigenesis. As EV research grows, it is of importance to have standardization of isolation, quality control, characterization and validation methods across studies along with reliable references to explore troubleshooting solutions. Therefore, our objective with this Research Note was to isolate EVs from multiple breast cancer cell lines and to describe and perform protocols for validation as outlined by the list of minimal information for studies of EVs (MISEV) from the International Society for Extracellular Vesicles.ResultsTo isolate EVs, two techniques were employed: ultracentrifugation and size exclusion chromatography. Ultracentrifugation yielded better recovery of EVs in our hands and was therefore used for further validation. In order to satisfy the MISEV requirements, protein quantification, immunoblotting of positive (CD9, CD63, TSG101) and negative (TGFβ1, β-tubulin) markers, nanoflow cytometry and electron microscopy was performed. With these experiments, we demonstrate that yield of validated EVs varied between different breast cancer cell lines. Protocols were optimized to accommodate for low levels of EVs, and various technical and troubleshooting suggestions are included for potential application to other cell types that may provide benefit to investigators interested in future EV studies.

Investigation of Clinical Course and Possible Drug Interactions in Patients with Multiple Sclerosis and Breast Cancer.

This study aims to investigate the clinical course and potential drug interactions of breast cancer patients diagnosed with multiple sclerosis (MS). Ten patients diagnosed with MS and breast cancer, who were followed up and treated in the authors' centre between January 2000 and December 2020, were retrospectively scanned from the Hospital's electronic registry system and included in the study. The patients' age, gender, history of MS diagnosis, drugs used, date of breast cancer diagnosis, stage at diagnosis, pathological features, treatment information, surgery types, recurrence or metastasis history and regions, and side effects observed during anticancer treatment were recorded. Key Words: Multiple sclerosis, Breast cancer, Drug-drug interactions.

Breast cancer cells promote osteoclast differentiation in an MRTF-dependent paracrine manner.

Bone is a frequent site for breast cancer metastasis. Conditioning of the local tumor microenvironment (TME) through crosstalk between tumor cells and bone resident cells in the metastatic niche is a major driving force for bone colonization of breast cancer cells. The vast majority of breast cancer-associated metastasis is osteolytic in nature, and RANKL-induced differentiation of bone marrow-derived macrophages to osteoclasts (OCLs) is a key requirement for osteolytic metastatic growth of cancer cells. In this study, we demonstrate that breast cancer cell-secreted factors stimulate RANKL-induced OCL differentiation of BMDMs requiring the function of Myocardin-related transcription factor (MRTF) in tumor cells. This is partly attributed to the critical role of MRTF in maintaining the basal cellular expression of connective tissue growth factor (CTGF), a pro-osteoclastogenic matricellular factor known to promote bone metastasis in human breast cancer. Supporting these in vitro findings, bioinformatics analyses of multiple human breast cancer transcriptome datasets reveal a strong positive correlation between CTGF expression and MRTF gene signature further establishing the relevance of our findings in a human disease context. By Luminex analyses, we show that MRTF depletion in breast cancer cells has a broad impact on OCL-regulatory cell-secreted factors that extends beyond CTGF. These findings, taken together with demonstration of MRTF-dependence for bone colonization breast cancer cells in vivo, suggest that MRTF inhibition could be an effective strategy to diminish OCL formation and skeletal involvement in breast cancer. In summary, this study highlights a novel tumor-extrinsic function of MRTF relevant to breast cancer metastasis.

Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.

Understanding signaling patterns of transformation and controlling cell phenotypes is a challenge of current biology. Here we applied a cell State Transition Assessment and Regulation (cSTAR) approach to a perturbation dataset of single cell phosphoproteomic patterns of multiple breast cancer (BC) and normal breast tissue-derived cell lines. Following a separation of luminal, basal, and normal cell states, we identified signaling nodes within core control networks, delineated causal connections, and determined the primary drivers underlying oncogenic transformation and transitions across distinct BC subtypes. Whereas cell lines within the same BC subtype have different mutational and expression profiles, the architecture of the core network was similar for all luminal BC cells, and mTOR was a main oncogenic driver. In contrast, core networks of basal BC were heterogeneous and segregated into roughly four major subclasses with distinct oncogenic and BC subtype drivers. Likewise, normal breast tissue cells were separated into two different subclasses. Based on the data and quantified network topologies, we derived mechanistic cSTAR models that serve as digital cell twins and allow the deliberate control of cell movements within a Waddington landscape across different cell states. These cSTAR models suggested strategies of normalizing phosphorylation networks of BC cell lines using small molecule inhibitors.

UM171 suppresses breast cancer progression by inducing KLF2

PurposeBreast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action.MethodsThe inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells.ResultsUM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture.ConclusionThese results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.

Joint effects of long-term exposure to multiple air pollutants and breast cancer risk.

10572 Background: Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effect of exposure to multiple air pollutants on breast cancer risk. We assessed the joint effects of multiple air pollutants and breast cancer risk. Methods: The study was based on a case-control study nested within the French E3N cohort, involving 5222 incident breast cancer cases and 5222 matched controls. For each woman, the average of the mean annual concentration estimates for eight air pollutants ((benzo(a)pyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO2), particulate matters (PM2.5, PM10), ozone) was estimated from cohort inclusion (in 1990) to the index date. We used Bayesian Profile Regression, which groups individuals according to their exposure profile and risk levels, and assigns a risk to each of these clusters. Odds ratios (OR) and their 95% credible intervals (CrI) were estimated. Results: Overall, 21 clusters were identified. The cluster characterized by low exposures to all pollutants, except ozone was taken as reference. A significant increase in breast cancer risk compared to the reference cluster was observed for 3 clusters, with the OR of 1.61 (CrI: 1.13;2.26), OR (1.00; 1.88), and OR 1.38 (1.00; 1.88) respectively. These three clusters share quite similar exposure profiles characterized by women in urban settings with high exposure to most pollutants, particularly to NO2, PM and PCB153. Conclusions: Overall, there is evidence of a positive joint effect of high level exposures to air several pollutants, namely NO2, PM and PCB153 and increased risk of breast cancer.