The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.

Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.

A MicroRNA targeting dicer for metastasis control.

Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery. In human breast cancer, high levels of miR-103/107 are associated with metastasis and poor outcome. Functionally, miR-103/107 confer migratory capacities in vitro and empower metastatic dissemination of otherwise nonaggressive cells in vivo. Inhibition of miR-103/107 opposes migration and metastasis of malignant cells. At the cellular level, a key event fostered by miR-103/107 is induction of epithelial-to-mesenchymal transition (EMT), attained by downregulating miR-200 levels. These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis.

Impact of Cold Ischemia on the Stability of 1H-MRS-Detected Metabolic Profiles of Ovarian Cancer Specimens.

Proton magnetic resonance spectroscopy (1H-MRS) of surgically collected tumor specimens may contribute to investigating cancer metabolism and the significance of the "total choline" (tCho) peak (3.2 ppm) as malignancy and therapy response biomarker. To ensure preservation of intrinsic metabolomic information, standardized handling procedures are needed. The effects of time to freeze (cold ischemia) were evaluated in (a) surgical epithelial ovarian cancer (EOC) specimens using high-resolution (HR) 1H-MRS (9.4 T) of aqueous extracts and (b) preclinical EOC samples (xenografts in SCID mice) investigated by in vivo MRI-guided 1H-MRS (4.7 T) and by HR-1H-MRS (9.4 T) of tumor extracts or intact fragments (using magic-angle-spinning (MAS) technology). No significant changes were found in the levels of 27 of 29 MRS-detected metabolites (including the tCho profile) in clinical specimens up to 2 h cold ischemia, besides an increase in lysine and a decrease in glutathione. EOC xenografts showed a 2-fold increase in free choline within 2 h cold ischemia, without further significant changes for any MRS-detected metabolite (including phosphocholine and tCho) up to 6 h. At shorter times (≤1 h), HR-MAS analyses showed unaltered tCho components, along with significant changes in lactate, glutamate, and glutamine. Our results support the view that a time to freeze of 1 h represents a safe threshold to ensure the maintenance of a reliable tCho profile in EOC specimens.

The curious phenomenon of dual-positive circulating cells: Longtime overlooked tumor cells.

The presence in the blood of patients with solid tumors of circulating cells expressing both epithelial and leukocyte markers (dual-positive cells, DPcells), has often been reported, though it has never been investigated in detail. A recent study suggested that DPcells are hybrid cells derived from the fusion of tumor cells with macrophages. Such fusion hybrids acquire macrophage-associated features endowing them with accelerated growth, increased motility, enhanced invasion activity and thus, a higher efficiency in metastasis formation. However, no direct evidence proving the tumor origin of circulating DPcells was provided in patients. Here we contribute a review of literature data on DPcells and on the hybrid theory with the aim of putting the current evidence both in a biological and clinical perspective and to generate new hypotheses on the mechanisms underlying tumor progression. To add further biological and clinical context to our literature review, we also report some preliminary data from our laboratory on the identification of DPcells in several solid tumors and confirmation of their malignant genotype, thus classifying them as DP-CTCs.

Transmission of SARS-CoV-2 in Surgical Smoke during Laparoscopy: A Prospective, Proof-of-concept Study.

STUDY OBJECTIVE: There are growing concerns regarding the potential risk of coronavirus disease transmission during surgery and in particular during minimally invasive procedures owing to the aerosolization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particles. However, no study has demonstrated this hypothesis. Here, we aimed to investigate the presence of SARS-CoV-2 in surgical smoke. DESIGN: A prospective pilot study. SETTING: A tertiary cancer center in northern Italy. PATIENTS: Overall, 17 patients underwent laparoscopic procedures for the management of suspected or documented gynecologic malignancies. The median age was 57 years (range 26-77). The surgical indications included endometrial cancer (n = 11), borderline ovarian tumor (n = 3), early-stage ovarian cancer (n = 1), stage IA cervical cancer after diagnostic conization (n = 1), and an ovarian cyst that turned out to be benign at final histologic examination (n = 1). INTERVENTIONS: We evaluated all consecutive women scheduled to have laparoscopic procedures for suspected or documented gynecologic cancers. The patients underwent planned laparoscopic surgery. At the end of the laparoscopic procedures (after extubation), we performed reverse transcription-polymerase chain reaction (RT-PCR) tests for the detection of SARS-CoV-2 from both the endotracheal tube and the filter applied on the trocar valve. MEASUREMENTS AND MAIN RESULTS: In 1 patient, both swab tests (endotracheal tube and trocar valve filter) showed amplification of the N gene on RT-PCR analysis. This case was considered to be a presumptive positive case. In another case, the RT-PCR analysis showed an amplification curve for the N gene only in the swab test performed on the filter. No ORF1ab amplification was detected. CONCLUSION: Our study suggested the proof of principle that SARS-CoV-2 might be transmitted through surgical smoke and aerosolized native fluid from the abdominal cavity.

Effect of body mass index on response to neo-adjuvant therapy in HER2-positive breast cancer: an exploratory analysis of the NeoALTTO trial.

BACKGROUND: Obesity is a risk factor for breast cancer (BC) development, recurrence, and death. In view of this, we aimed to investigate the clinical value of obesity in BC patients treated with anti-HER2 therapies in the NeoALTTO trial, which randomized 455 patients to neo-adjuvant lapatinib, trastuzumab, or their combination plus paclitaxel. METHODS: Patients were classified according to their basal body mass index (BMI) into underweight (< 18.5 kg/m2), normal (≥ 18.5; < 25 kg/m2), overweight (≥ 25; < 30 kg/m2), and obese (≥ 30 kg/m2) WHO categories. Univariate and multivariate logistic regression analyses were performed using BMI as a categorical variable. Pathological complete response (pCR) and event-free survival (EFS) were the NeoALTTO primary and secondary outcomes, respectively. RESULTS: Among 454 patients analyzed, 14 (3%), 220 (48%), 137 (30%), and 83 (18%) were classified as underweight, normal weight, overweight, and obese, respectively; 231 (51%) and 223 (49%) had hormone receptor (HR)-positive and HR-negative primary tumors; 160 (35%) achieved pCR. In the overall patient population, no association was found between BMI groups and pCR, as we reported pCR rates of 57.1%, 35%, 30.7%, and 39.8% in underweight, normal weight, overweight, and obese cases, respectively. In contrast, in HR-positive tumors, overweight or obesity was generally associated with decreased likelihood of achieving a pCR independently of other clinical variables, including planned surgery, nodal status, and tumor size (odds ratio [OR] = 0.55, 95%CI 0.30-1.01, as compared to normal or underweight; p = 0.053); notably, no differential effect of BMI with respect to pCR was observed in HR-negative cases (odds ratio [OR] = 1.30, 95%CI 0.76-2.23, as compared to normal or underweight; p = 0.331), resulting in a statistically significant interaction between BMI and HR status (p = 0.036). There was no association between BMI and EFS neither in the overall nor in the HR-positive population, but this analysis was under-powered. CONCLUSIONS: NeoALTTO patients overweight or obese at baseline and with HR-positive primary BC appeared less likely to achieve pCR after neo-adjuvant anti-HER2 therapies. This finding paves the way to future research in targeting the interplay between HER2/HR signaling and metabolism.

Circulating Tumor Cells (CTCs) Heterogeneity in Metastatic Breast Cancer: Different Approaches for Different Needs.

In metastatic breast cancer the role of circulating tumor cells (CTCs) enumeration for predicting clinical outcome is supported by many studies, most of them dealing with strictly epithelial cells. However, it is becoming clear that CTCs are a heterogeneous cell population characterized by plasticity and including also cells which have lost the epithelial phenotype. Here we review literature data on CTC heterogeneity both at phenotype and at molecular level and discuss the possible contribute of single cell analyses in precision medicine. We conclude with some remarks about the steps still necessary to achieve clinical validity and utility when considering also CTC phenotypic and molecular heterogeneity beyond a simple enumeration.

Analysis of Single Circulating Tumor Cells in Renal Cell Carcinoma Reveals Phenotypic Heterogeneity and Genomic Alterations Related to Progression.

Circulating tumor cells (CTCs) are promising biomarkers for prognosis, therapeutic response prediction, and treatment monitoring in cancer patients. Despite its epithelial origin, renal cell carcinoma (RCC) shows low expression of epithelial markers hindering CTC-enrichment approaches exploiting epithelial cell surface proteins. In 21 blood samples serially collected from 10 patients with metastatic RCC entering the TARIBO trial, we overcame this limitation using the marker-independent Parsortix™ approach for CTC-enrichment coupled with positive and negative selection with the DEPArray™ with single cell recovery and analysis for copy number alterations (CNA) by next generation sequencing NGS. Two CTC subpopulations were identified: epithelial CTC (eCTC) and non-conventional CTC (ncCTC) lacking epithelial and leukocyte markers. With a threshold ≥1CTC/10 mL of blood, the positivity rates were 28% for eCTC, 62% for ncCTCs, and 71% considering both CTC types. In two patients with detectable eCTCs at baseline, progression free survival was less than 5 months. In an index case, hierarchical structure by translational oncology (TRONCO) identified three clones among 14 CTCs collected at progression and at baseline, each containing cells with a 9p21.3loss, a well-known metastasis driving subclonal alteration. CTCs detection in RCC can be increased by marker-independent approaches, and CTC molecular characterization can allow detection of subclonal events possibly related to tumor progression.

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy.

Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%-68%), and 44% (95%CI 22%-69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23-9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%-81%) and 0% (95%CI 0%-31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.

How to study and overcome tumor heterogeneity with circulating biomarkers: The breast cancer case.

Breast cancer ranks first among female cancer-related deaths in Western countries. As the primary tumor can often be controlled by surgical resection, the survival of women with breast cancer is closely linked to the incidence of distant metastases. Molecular screening by next generation sequencing highlighted the spatial and temporal heterogeneity of solid tumors as well as the clonal evolution of cancer cells during progression and under treatment pressure. Such findings question whether an optimal assessment of disease progression and a screening for druggable mutations should be based on molecular features of primary or recurrent/metastatic lesions and therefore represent a crucial element for failure or success of personalized medicine. In fact, new targeted therapies may induce only short-term benefit annulled by the emergence of resistant clones with new driver mutations which would need to be rapidly and reliably identified. Serial tissue sampling is therefore essential but, unfortunately, also represents a problem since biopsies from solid lesions, which are invasive and potentially painful and risky, cannot be easily repeatedly sampled, are inaccessible or may not fully reflect tumor heterogeneity. The need to early detect and strike this "moving target" is now directing the scientific community toward liquid biopsy-based biomarkers, which include circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA), can be repeatedly assessed through non-invasive and easy-to-perform procedures and may act as reliable read-outs of functional and molecular features of recurrent/metastatic lesions. In this review we summarize the outcome of CTCs and ctDNA in breast cancer, with special reference on their role on unveiling and overcoming tumor heterogeneity, on their potential relevance for tumor surveillance and monitoring, and for the selection of therapeutic options. Finally, we propose integration between blood-based molecular and clinical approaches for monitoring disease progression according to the specific pattern of recurrence of the most aggressive breast cancer molecular subtypes.

Biobanks and scientists: supply and demand.

The biobanks, providers of biospecimens, and the scientists, users of biological material, are both strategic actors in translational medicine but the communication about those two subjects seems to be delicate. Recently, biobank managers from US and Europe stressed the danger of underuse of biospecimens stored in their biobanks thus stimulating the debate about innovative ways to collect samples and to communicate their availability. We hypothesize that the already stored collections meet the interest of present scientists only in specific situations. Serial biospecimens from patients with large associated clinical data concerning voluptuary habits, environmental exposure, anthropomorphic information are needed to meet the even more specific projects the scientists are planning. The hypothesis of activation of specific sections in ranked journals aimed to facilitate the communication between partners interested in finding/collecting ad hoc biospecimens is discussed.

Dissecting Time- from Tumor-Related Gene Expression Variability in Bilateral Breast Cancer.

Metachronous (MBC) and synchronous bilateral breast tumors (SBC) are mostly distinct primaries, whereas paired primaries and their local recurrences (LRC) share a common origin. Intra-pair gene expression variability in MBC, SBC, and LRC derives from time/tumor microenvironment-related and tumor genetic background-related factors and pairs represents an ideal model for trying to dissect tumor-related from microenvironment-related variability. Pairs of tumors derived from women with SBC (n = 18), MBC (n = 11), and LRC (n = 10) undergoing local-regional treatment were profiled for gene expression; similarity between pairs was measured using an intraclass correlation coefficient (ICC) computed for each gene and compared using analysis of variance (ANOVA). When considering biologically unselected genes, the highest correlations were found for primaries and paired LRC, and the lowest for MBC pairs. By instead limiting the analysis to the breast cancer intrinsic genes, correlations between primaries and paired LRC were enhanced, while lower similarities were observed for SBC and MBC. Focusing on stromal-related genes, the ICC values decreased for MBC and were significantly different from SBC. These findings indicate that it is possible to dissect intra-pair gene expression variability into components that are associated with genetic origin or with time and microenvironment by using specific gene subsets.

Development of a Protocol for Single-Cell Analysis of Circulating Tumor Cells in Patients with Solid Tumors.

Genomic characterization of circulating tumor cells (CTCs) enables the monitoring of tumor progression and of adaption occurring during treatment. CTC molecular characterization represents indeed a precious tool to implement in the clinical practice for better dealing with acquired resistance to systemic treatment and tumor evolution. Unfortunately CTCs are very rare and enrichments from blood samples and subsequent identification of these cells are technically very challenging. We describe here the main steps leading to the development of a technical protocol for visualization, enumeration and recovery of single CTCs exploiting the recently developed DEPArray™platform. Our description of the technical workflow starts with evaluation of pre-analytical aspects related to blood sample collection warning about the possible effects on immunoreactivity profiles which may bias the interpretation. Subsequently, other CTC-enrichment approaches are critically discussed and compared in relation to their performances with the DEPArray™. Identification of CTCs represents another critical point due to their heterogeneity and due to the still-to-be clarified role of different subpopulations, typically epithelial, mesenchymal or mixed. Finally, issues related to single cell analysis are illustrated. The chapter ends with an overview of results obtained on real clinical samples which support the reliability of the protocol and its transferability to the daily clinical routine.

Cell cycle dependent oscillatory expression of estrogen receptor-α links Pol II elongation to neoplastic transformation.

Decades of studies provided a detailed view of the mechanism of estrogen receptor-α (ERα) regulated gene transcription and the physio-pathological relevance of the genetic programs controlled by this receptor in a variety of tissues. However, still limited is our knowledge on the regulation of ERα synthesis. Preliminary observations showed that the expression of ERα is cell cycle regulated. Here, we have demonstrated that a well described polymorphic sequence in the first intron of ERα (PvuII and XbaI) has a key role in regulating the ERα content in cycling cells. We have shown that the RNA Pol II (Pol II) elongation is blocked at the polymorphic site and that the proto-oncogene c-MYB modulates the release of the pausing polymerase. It is well known that the two SNPs are associated to an increased risk, progression, survival and mortality of endocrine-related cancers, here we have demonstrated that the c-MYB-dependent release of Pol II at a specific phase of the cell cycle is facilitated by the px haplotype, thus leading to a higher ERα mitogenic signal. In breast cancer, this mechanism is disrupted when the hormone refractory phenotype is established; therefore, we propose this oscillator as a novel target for the development of therapies aimed at sensitizing breast cancer resistant to hormonal treatments. Because PvuII and XbaI were associated to a broad range physio-pathological conditions beside neoplastic transformation, we expect that the ERα oscillator contributes to the regulation of the estrogen signal in several tissues.

Implications of stemness-related signaling pathways in breast cancer response to therapy.

There is accumulating evidence that breast cancer may arise from a small subpopulation of transformed mammary stem/progenitor cells, termed breast cancer-initiating cells (BCICs), responsible for initiation and maintenance of cancer. BCICs have been identified in clinical specimens based on CD44(+)/CD24(-/low) membrane expression and/or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), or isolated and in vitro propagated as non-adherent spheres. This cell population has been demonstrated to be able to recreate, when injected in mice even at very low concentrations, the same histopathological features of the tumor they were derived from and to escape from current therapeutic strategies. Alterations in genes involved in stemness-related pathways, such as Wnt, Notch, and Sonic Hedgehog, have been proven to play a role in breast cancer progression. Targeting these key elements represents an attractive option, with a solid rationale, although possible concerns may derive from the poor knowledge of tolerance and efficacy of inhibiting these mechanisms without inducing severe side effects. In addition, efforts to develop alternative BCIC-targeted therapies against stemness markers (CD44 and ALDH1) and molecules involved in regulating EMT- and HER2-related pathways, or able to reverse the multi-drug resistance phenotype, or to induce differentiation and to control cell survival pathways are currently ongoing and encouraging results from pre-clinical studies have already been obtained using in vitro and in vivo models.

Tumor-extracellular matrix interactions: Identification of tools associated with breast cancer progression.

Several evidences support the concept that cancer development and progression are not entirely cancer cell-autonomous processes, but may be influenced, and possibly driven, by cross-talk between cancer cells and the surrounding microenvironment in which, besides immune cells, stromal cells and extracellular matrix (ECM) play a major role in regulating distinct biologic processes. Stroma and ECM-related signatures proved to influence breast cancer progression, and to contribute to the identification of tumor phenotypes resistant to cytotoxic and hormonal treatments. The possible clinical implications of the interplay between tumor cells and the microenvironment, with special reference to ECM remodelling, will be discussed in this review.

Osteopontin, E-cadherin, and ß-catenin expression as prognostic biomarkers in patients with radically resected gastric cancer.

A correlation between osteopontin, E-cadherin, ß-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, ß-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapse-free and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal ß-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.

Proposal of supervised data analysis strategy of plasma miRNAs from hybridisation array data with an application to assess hemolysis-related deregulation.

BACKGROUND: Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is available, i.e., that of hemolysis-related miRNAs deregulation, so as to compare our results with existing evidence. RESULTS: We developed a structured strategy with innovative applications of existing bioinformatics methods for supervised analyses including: 1) the combination of two statistical (t- and Anderson-Darling) test results to detect miRNAs with significant fold change or general distributional differences in class comparison, which could reveal hidden differential biological processes worth to be considered for building predictive tools; 2) a bootstrap selection procedure together with machine learning techniques in class prediction to guarantee the transferability of results and explore the interconnections among the selected miRNAs, which is important for highlighting their inherent biological dependences. The strategy was applied to develop a classifier for discriminating between hemolyzed and not hemolyzed plasma samples, defined according to a recently published hemolysis score. We identified five miRNAs with increased expression in hemolyzed plasma samples (miR-486-5p, miR-92a, miR-451, miR-16, miR-22). CONCLUSIONS: We identified four miRNAs previously reported in the literature as hemolysis related together with a new one (miR-22).which needs further investigations. Our findings confirm the validity of the proposed strategy and, in parallel, the hemolysis score capability to be used as pre-analytic hemolysis detector. R codes for implementing the approaches are provided.

YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK- and CHOP-mediated DR5 upregulation.

Because available treatments have limited efficacy in triple-negative breast cancer (TNBC), the identification of new therapeutic strategies to improve patients' outcome is urgently needed. In our study, we investigated the effects of the administration of the small molecule selective survivin suppressant YM155, alone or in association with CD34+ cells transduced with a replication-deficient adenovirus encoding the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene (CD34-TRAIL+ cells), in three TNBC cell models. YM155 exposure significantly impaired TNBC cell growth and selectively modulated survivin expression at both mRNA and protein level. In addition, co-culturing YM155-treated TNBC cells with CD34-TRAIL+ cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with single treatments. Such a chemosensitizing effect was observed only in TNBC cells inherently expressing DR5 and relied on the ability of YM155 to upregulate DR5 expression through a p38 MAPK- and CHOP-dependent mechanism. YM155/CD34-TRAIL+ combination also showed a significant inhibitory effect on the growth of DR5-expressing TNBC cells following xenotransplantation into NOD/SCID mice, in the absence of toxicity. Overall, our data (i) provide, for the first time, evidence that YM155 sensitizes TNBC cells to CD34-TRAIL+ cells-induced apoptosis by a mechanism involving the downregulation of survivin and the simultaneous p38 MAPK- and CHOP-mediated upregulation of DR5, and (ii) suggest the combination of YM155 with TRAIL-armed CD34+ progenitor cells as a promising therapeutic option for patients with TNBC expressing DR5.