Glyoxalase 1 knockdown induces age-related ß-cell dysfunction and glucose intolerance in mice.

Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age-dependent impairment of glucose tolerance and glucose-stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80-positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP-1 and TNF-α), part of the senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 ß-cells to MGO confirms its casual role on ß-cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.

Interaction Proteomics Identifies ERbeta Association with Chromatin Repressive Complexes to Inhibit Cholesterol Biosynthesis and Exert An Oncosuppressive Role in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERß) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERß under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERß in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERß of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERß association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERß association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERß in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.

Noncoding RNAs within the HOX gene network in tumor pathogenesis and progression.

HOX genes are involved with normal development, cell identity, cell differentiation, cell metabolism, apoptosis, autophagy as well as with diseases such as tumor pathogenesis and progression. In particular, the genes belonging to HOX paralogous 13 seem to carry out a relevant role in both tumor development and disease progression. In recent years, several noncoding RNAs (ncRNA) sequences have been identified in HOX loci, including long noncoding RNA (lncRNA) and microRNA (miRNA), highly conserved during evolution. Many studies have shown that specific intergenic ncRNAs in HOX loci could directly modulate HOX genes expression in normal and pathological conditions. In the present review we attempt to describe the role of these ncRNAs, through the regulation of the HOX gene network, in normal cell biology, and, with particular emphasis, in diseases such as in cancer pathogenesis and progression.

Interleukin-8, but not the Related Chemokine CXCL1, Sustains an Autocrine Circuit Necessary for the Properties and Functions of Thyroid Cancer Stem Cells.

Interleukin-8 (IL-8/CXCL8) mediates its biological effects through two receptors, CXCR1 and CXCR2. While CXCR1 recognizes IL-8 and granulocyte chemotactic protein-2, CXCR2 binds to multiple chemokines including IL-8, CXCL1, 2 and 3. Both IL-8 and CXCL1 have been implicated in the neoplastic features of thyroid cancer (TC). Here, we assessed the role of the autocrine circuits sustained by IL-8 and CXCL1 in determining TC stem cell (TC SC) features. Using immunohistochemistry, we found that thyroid epithelial cancerous, but not normal, cells stained positive for IL-8, whose levels correlated with lymph-nodal metastases. We assessed the expression of endogenous IL-8 and CXCL1, by ELISA assays, and of their receptors CXCR1 and CXCR2, by flow cytometry, in a panel of TC cell lines. These molecules were expressed in TC cell lines grown in adherence, and at higher levels also in thyrospheres enriched in stem-like cells. RNA interference demonstrated that IL-8/CXCR1, but not CXCL1/CXCR2, is crucial for the sphere-forming, self-renewal and tumor-initiating ability of TC cells. Accordingly, treatment of TC cells with IL-8, but not with CXCL1, potentiated cell stemness. We identified CD34 as an IL-8-induced gene and as a TC SC marker, since it was overexpressed in thyrospheres compared to adherent cells. Moreover, CD34 is required for the efficient sphere-forming ability and tumorigenicity of TC cells. Our data indicate that IL-8, but not the CXCL1 circuit, is critical for the regulation of TC SCs, and unveils novel potential targets for the therapy of as yet untreatable forms of TC. Stem Cells 2017;35:135-146.

Sex Hormone Receptors in Benign and Malignant Salivary Gland Tumors: Prognostic and Predictive Role.

The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting information about the role of the estrogen receptor alpha (ERα), progesterone receptor (PgR) and androgen receptor (AR) has been described and in most cases the use of sex hormone antagonists is not contemplated in clinical practice. In this study, we analyzed a panel of sex hormone receptors that have not been widely investigated in SGTs-ERα, PgR, AR, but also ERß and GPR30-to define their expression pattern and their prognostic and predictive value in a case series of 69 benign and malignant SGTs. We showed the aberrant expression of AR in mucoepidermoid and oncocytic carcinoma, a strong relation between cytoplasmic ERß expression and tumor grade, and a strong correlation between nuclear GPR30 expression and disease-free survival (DFS) of SGT patients.

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.

BACKGROUND: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. METHODS: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. RESULTS: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. CONCLUSIONS: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients.

Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an "approved for diagnostic assay" antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan-Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC.

Coexistence of granular cell tumor and invasive ductal breast cancer in contralateral breasts: a case report.

Granular cell tumor (GCT) is a benign tumor of the breast that can mimic, on breast imaging, invasive carcinomas. Biological evolution of mammary GCT is unknown, especially if it is associated with an invasive carcinoma in the same or contralateral breast. This report details the morphological features of these synchronous lesions highlighting their biological characteristics and suggesting an appropriate follow up.

B-cell non-Hodgkin lymphoma of the breast in Waldenström's macroglobulinemia: a case report.

Background: Non-Hodgkin lymphoma (NHL) of the breast is a rare disease and can occur amongst patients affected by Waldenström's Macroglobulinemia (WM). WM is an indolent B-cell lymphoproliferative disorder with an overall incidence of about 1/100,000 in Europe. Breast imaging is not specific to breast lymphoma that often mimics benign lesions. The diagnosis is based on breast biopsy, the presence of MYD88L265P somatic mutation and immunoglobulin M (IgM) paraprotein detectable in the setting of lymphoplasmacytic infiltration by bone marrow (BM) biopsy. Case Description: A 60-year-old woman with personal and familial history of monoclonal gammopathy of undetermined significance (MGUS) and a lump in her right breast was referred to our hospital. Standard imaging showed round mass with smooth edges. The lump was biopsied and the pathology examination showed lymphoplasmacytic lymphoma (LPL) of the breast which led to final the diagnosis of WM. Conclusions: Lymphoma of the breast is a rare disease, often misdiagnosed because of the lack of specific features at mammogram and ultrasound. Core biopsy is crucial to make diagnosis of breast lymphoma and early diagnosis of WM has been shown to improve overall survival (OS). A comprehensive approach is required in order to assess patients affected by blood disorders presenting with a new breast mass that can lead to diagnosis of breast lymphoma.

Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer.

M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC). Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-ß enhancement, IL-17F secretion, and extracellular vesicle protein content modulation. We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

Long Non-Coding RNA HOTAIR in Breast Cancer Therapy.

Breast cancer (BC) is the most common cancer type among women, and morbidity and mortality rates are still very high. Despite new innovative therapeutic approaches for all BC molecular subtypes, the discovery of new molecular biomarkers involved in tumor progression has been fundamental for the implementation of personalized treatment strategies and improvement of patient management. Many experimental studies indicate that long non-coding RNAs (lncRNAs) are strongly involved in BC initiation, metastatic progression, and drug resistance. In particular, aberrant expression of HOX transcript antisense intergenic RNA (HOTAIR) lncRNA plays an important role in BC contributing to its progression and represents a predictor of BC metastasis. For its proven prognostic value, HOTAIR could represent a potential therapeutic target in BC. In the present review, we summarize the role of HOTAIR in cancer progression and drug resistance, in particular in BC, and we illustrate the main approaches for silencing it.

Molecular characterization of a bladder pleomorphic rhabdomyosarcoma in an adult patient.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare but highly aggressive soft tissue tumor, accounting for 3% of soft tissue sarcomas. PRMS is the most frequent subtype of RMS in adulthood and it is mainly located in the large muscles of the extremities, particularly the lower limbs and the trunk, more rarely in other locations especially in the bladder. At our knowledge, only six cases of adult pleomorphic rhabdomyosarcoma of the bladder have been reported in the literature. In this study, we report a case of PRMS of bladder with a very poor prognosis. In fact, the patient died a month after surgery. The tumor was characterized by poorly differentiated, medium-sized sometimes rhabdoid cells, mixed with large-sized and pleomorphic elements with evident anisonucleosis, and with large areas of necrosis. We used an extensive immunohistochemical panel to exclude other tumors much more frequently reported at this site. The positivity for myogenic markers such as actin, desmin, myogenin and MyoD1 allowed the correct diagnosis. Furthermore, since preliminary studies highlighted a series of specific molecular alterations in PMRS cell lines, we analyzed a panel of specific mutations and gene rearrangements by RT-PCR and FISH methods. We showed a copy gains of CCND1 and MALT genes in our samples, suggesting an accurate molecular characterization of PRMS to establish a better management of patients and new therapeutic opportunities.

Novel Aptamers Selected on Living Cells for Specific Recognition of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a high heterogeneous group of tumors with a distinctly aggressive nature and high rates of relapse. So far, the lack of any known targetable proteins has not allowed a specific anti-tumor treatment. Therefore, the identification of novel agents for specific TNBC targeting and treatment is desperately needed. Here, by integrating cell-SELEX (Systematic Evolution of Ligands by EXponential enrichment) for the specific recognition of TNBC cells with high-throughput sequencing technology, we identified a panel of 2'-fluoropyrimidine-RNA aptamers binding to TNBC cells and their cisplatin- and doxorubicin-resistant derivatives at low nanomolar affinity. These aptamers distinguish TNBC cells from both non-malignant and non-TNBC breast cancer cells and are able to differentiate TNBC histological specimens. Importantly, they inhibit TNBC cell capacity of growing in vitro as mammospheres, indicating they could also act as anti-tumor agents. Therefore, our newly identified aptamers are a valuable tool for selectively dealing with TNBC.

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor ß (PDGFRß) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRß aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRß aptamer and anti-PD-L1 mAbs in TNBC. METHODS: The targeting ability of the anti-human PDGFRß aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRß aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. RESULTS: We show that the PDGFRß aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells. CONCLUSION: Co-treatment of PDGFRß aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRß/PD-L1 co-targeting combination therapy in TNBC.

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERß) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERß is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERß-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERß, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERß+and 32 ERß- primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERß+ compared to ERß- tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERß+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERß in TNBC cells.

Morphological and pathological features of basal-like breast cancer.

Basal-like breast cancer (BLBC) is characterized by high grade, high mitotic indices, presence of central necrotic or fibrotic zones, and lymphocytic infiltrate. Patients presenting with BLBC have a poor prognosis and a short-term disease-free and overall survival. BLBCs may include different histological types of breast cancers but the most common histological type is represented by invasive ductal carcinomas of no special type (IDC-NST). Typical immunohistochemical markers for these tumors are basal-type cytokeratin markers such as CK5/6, CK14, CK17, but several BLBCs also express luminal-type CKs, such as CK8/18, CK19. Different molecular alterations, including BRCA1 dysfunction, p53 mutations, up-regulation of EGFR, inactivation of PTEN and the aberrant expression of many non-coding RNAs molecules are detected in BLBC cells suggesting the possibility of defining new targeted therapeutic strategies for this tumor type.

LncRNA HOTAIR up-regulation is strongly related with lymph nodes metastasis and LAR subtype of Triple Negative Breast Cancer.

Triple-negative breast cancers (TNBCs) represent a heterogeneous disease characterized by several molecular subtypes with different prognoses and responses to therapy. For a correct clinical management of TNBC patients the knowledge of the gene regulation mechanisms related to tumor progression and drug response has become fundamental. LncRNAs regulate gene expression through various processes, including chromatin modification, transcription and post-transcription and they are emerging as important cancer biomarkers being involved in tumor pathogenesis, metastatic progression and drug resistance. In this study we aimed to analyze the expression of the lncRNA HOTAIR, mainly involved in breast cancer disease, in a large case series of TNBC patients. We used ISH methods by a RNA probe to better define its staining in tumor tissues and its relation with clinical-pathological parameters and outcomes of patients. Our results show that high HOTAIR expression in tumor tissues is strongly correlated with lymph nodes metastasis (LNM) (p=0.039), as reported also for other tumor types, and has a direct strong association with Androgen Receptor (AR) expression (p= 0.019). These data confirm the prognostic role of HOTAIR in TNBC, and, its involvement in the regulation of AR pathway, suggests the possibility to establish new therapeutic strategies for AR+TNBC patients.

AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

LncRNA HOTAIR Polymorphisms Association with Cancer Susceptibility in Different Tumor Types.

Single nucleotide polymorphisms (SNPs) in non-coding RNAs (ncRNA) molecules affect gene and protein expression and generate genetic variability influencing the risk of tumor diseases. HOTAIR locates at the heart of the cell memory gene program and represents a prototype of long non coding RNA (LncRNA) due to its capacity to regulate in-trans a distant chromosome landscape. Aberrant expression of HOTAIR is frequently associated with pathogenesis and mostly with metastatic progression of several human cancers. Different polymorphisms, particularly present in intronic sequences, as well as in promoter regions of HOTAIR, are often associated with its aberrant expression, patient prognosis, and cancer susceptibility in different tumor phenotypes. In this minireview, we have summarized the main SNPs in HOTAIR sequence and their relation with cancer risk in several types of solid tumors.

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRß aptamer.

While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor ß (PDGFRß) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition. Methods: Immunohistochemical analysis for PDGFRß expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRß aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRß was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRß aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer. Results: Here, we present novel data showing that tumor cell expression of PDGFRß identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRß in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRß aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases. Conclusions: We propose PDGFRß as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRß aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.