ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) contributes greatly to mortality of breast cancer, demanding new targetable options. We have shown that TNBC patients have high ΔNp63 expression in tumors. However, the function of ΔNp63 in established TNBC is yet to be explored. In current studies, targeting ΔNp63 with inducible CRISPR knockout and Histone deacetylase inhibitor Quisinostat showed that ΔNp63 is important for tumor progression and metastasis in established tumors by promoting myeloid-derived suppressor cell (MDSC) survival through tumor necrosis factor alpha. Decreasing ΔNp63 levels are associated with decreased CD4+ and FOXP3+ T-cells but increased CD8+ T-cells. RNA sequencing analysis indicates that loss of ΔNp63 alters multiple MDSC properties such as lipid metabolism, chemotaxis, migration, and neutrophil degranulation besides survival. We further demonstrated that targeting ΔNp63 sensitizes chemotherapy. Overall, we showed that ΔNp63 reprograms the MDSC-mediated immunosuppressive functions in TNBC, highlighting the benefit of targeting ΔNp63 in chemotherapy-resistant TNBC.

Treatment of neovascular age-related macular degeneration within 48 h from diagnosis improves long-term functional outcome.

PURPOSE: To evaluate long-term visual and anatomical outcomes in neovascular age-related macular degeneration (nAMD) patients treated with anti-vascular endothelial growth factor (VEGF) agents depending on the time delay from confirmed diagnosis to treatment initiation. MATERIALS AND METHODS: Seventy-three nAMD patients (73 eyes) treated with anti-VEGF agents for 12 months using the pro re nata regimen were included in this retrospective longitudinal study. Patients were split into 3 groups according to the time from diagnosis to first anti-VEGF injection: < 48 h (group 1); 48 h-7 days (group 2); > 7 days (group 3). Decimal best-corrected visual acuity (VA) and macular thickness (MT) were recorded at baseline and 1-2-, 3-4-, 6- and 12-month later. Furthermore, age, gender as well as the applied treatment and number of injections after 12 months of treatment were also registered and compared. RESULTS: Long-term effect of the treatment demonstrated enhanced VA in group 1 patients compared with the rest of groups after 1-2-, 6-, and 12-month follow-up (P < 0.05). Positive effects of early treatment were additionally corroborated by the augmented percentage of patients with normal VA in the group 1 respect to the rest of groups over studied time points (P < 0.05). Moreover, the VA gain in nAMD at group 1 was obtained with a mean of 3.7 intravitreal injections over 1-year follow-up period. Regarding MT, non-significant difference was observed among groups. CONCLUSIONS: An early initial treatment with VEGF inhibitors is critical to achieve the best functional benefits of this therapy in new-onset nAMD patients.

Manejo de fracturas abiertas de tibia en Cuba / Management of Open Tibial Fractures in Cuba

Introducción: Las fracturas abiertas de tibia son un subconjunto de la carga de traumatismos en América Latina. Se examinaron cuestiones relacionadas con el tratamiento potencialmente críticas en Cuba, país con recursos limitados, pero con un programa nacional de salud estandarizado, coherencia en educación y similitudes de programas de posgrado. Objetivos: Describir los patrones de tratamiento de la fractura abierta de tibia en Cuba, y comparar las características del manejo agudo y tardío en siete provincias del país. Métodos: Se encuestaron 67 cirujanos ortopédicos para evaluar cuatro aspectos en el tratamiento de la fractura abierta: profilaxis antibiótica, irrigación y desbridamiento, estabilización y tratamiento de heridas. Se utilizó el método de muestreo por conveniencia para identificar a los cirujanos y el análisis se realizó mediante la prueba exacta de Fisher (p < 0,05). Resultados: Se administraron antibióticos posoperatorios durante más de 72 horas para las fracturas GA-I/II (49 por ciento) y las fracturas GA-III (70 por ciento). Los cirujanos de La Habana (n= 32) utilizaron con más frecuencia la fijación interna primaria para las fracturas GA-I/II, que los cirujanos en las restantes provincias (n= 35) (64,3 porciento vs. 30,3 por ciento, p= 0,008). Los cirujanos de otras provincias realizaron cierre primario en el momento de la fijación definitiva de fracturas GA-I /II con más frecuencia que los de La Habana (62,9 por ciento vs. 32,3 por ciento, p= 0,013). Para fracturas GA-III, la mayoría de los cirujanos habaneros (88,6 %), al igual que los de las restantes provincias (96,8 por ciento) prefirieron realizar cierre diferido.Conclusiones: El tratamiento de fracturas abiertas de tibia en Cuba es generalmente consistente con otros países de América Latina. Se describen las características del manejo de fracturas abiertas de tibia en Cuba y se comparan las diferencias en los métodos de estabilización y tratamiento de heridas entre provincias, lo cual resulta útil para evaluar si son resultado de diferencias en la práctica quirúrgica, o en la disponibilidad de recursos. Esto representa una ayuda al abordar las formas de optimizar la atención al paciente, a través de la capacitación especializada y la asignación de los recursos(AU)

Introduction: Open tibia fractures are a significant subset of the overall trauma burden in Latin America. Latin American countries vary in their access to orthopaedic care resources, and country-specific orthopaedic recommendations are necessary. Cuba, a country with limited resources, has a standardized national health program, consistencies in education, and similarities across post-graduate training programs. This study aimed to identify management preferences for open tibia factures in Cuba. Objectives: To describe the treatment of open tibial fractures in Cuba, and to compare the characteristics of acute and delayed management across seven Cuban provinces. Methods: Sixty-seven orthopaedic surgeons were surveyed to evaluate four aspects of open fracture management, regarding antibiotic prophylaxis, irrigation and debridement, stabilization, and wound management. The convenience sampling method was used to identify surgeons and the analysis was performed using Fisher's exact test (p <0.05). Results: Postoperative antibiotics were administered for more than 72 hours for GA-I / II fractures (49 pecent) and GA-III fractures (70 percent). Surgeons in Havana (n = 32) used primary internal fixation for GA-I / II fractures more frequently than surgeons in the remaining provinces (n = 35) (64.3 pecent vs. 30.3 percent p = 0.008). Surgeons from other provinces performed primary closure at the time of definitive fixation of GA-I / II fractures more frequently than those from Havana (62.9 percent vs. 32.3 percent, p = 0.013). For GA-III fractures, the majority of Havana surgeons (88.6 percent), as well as those of the remaining provinces (96.8 percent) preferred to perform deferred closure. Conclusions: The treatment of open tibial fractures in Cuba is generally consistent with other Latin American countries. The characteristics of the management of open tibial fractures in Cuba are described and differences in wound stabilization and treatment methods between provinces are compared, which is useful to assess whether they are the result of differences in surgical practice, or in availability of resources. This is helpful in addressing ways to optimize patient care through specialized training and resource allocation(AU)

Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.

Artrodesis transcalcánea con injerto libre del peroné por seudoartrosis de tibia distal / Transcalcaneal Arthrodesis with Free Fibula Graft for Distal Tibial Nonunion

RESUMEN Introducción: Las fracturas abiertas del tercio distal de tibia o pilón son poco frecuentes, en nuestro medio se producen por traumas de alta energía como los accidentes de tránsito, y pueden ser de distintos grados según su envergadura. Entre las complicaciones frecuentes están la seudoartrosis, deformidades y artritis postraumática. Cuando el dolor es refractario a los analgésicos están indicadas las artrodesis. Objetivo: Presentar los resultados del tratamiento realizado en un paciente con seudoartrosis distal de tibia y artritis postraumática del tobillo, dolorosa, con gran lesión de partes blandas, por lo que fue imposible realizar los procedimientos quirúrgicos habituales. Presentación del caso: Se realizó artrodesis de las articulaciones tibio-peronea-astragalina-calcánea, mediante un injerto libre del peroné autólogo, compresión, y estabilización con un fijador externo RALCA®; se asoció un campo electromagnético pulsátil para acelerar la formación del callo óseo y disminuir el dolor posquirúrgico. Durante dos años se le hizo seguimiento. Conclusiones: Se logró el objetivo del tratamiento al fusionar la articulación tibiotarsiana, comenzar el apoyo precoz y su capacidad funcional. Los resultados demuestran además los beneficios de la compresión realizada con los fijadores externos en las artrodesis; el uso del campo electromagnético asociado aceleró la osteogénesis, se consiguió la consolidación ósea, la estabilización, disminuyó el edema y el dolor, además la reincorporación del paciente a la sociedad. No se encontró en la bibliografía revisada otra técnica quirúrgica similar(AU)

ABSTRACT Introduction: Open fractures of the distal third of the tibia or pilon are rare, in our environment they are caused by high-energy traumas such as traffic accidents, and can be of different degrees depending on their size. Common complications include nonunion, deformities, and post-traumatic arthritis. When pain is refractory to analgesics, arthrodesis is indicated. Objective: To report the results of the treatment carried out in a patient with distal tibial pseudoarthrosis and post-traumatic arthritis of the ankle, painful, with a large soft tissue injury, which made it impossible to perform the usual surgical procedures. Case report: Arthrodesis of the tibiofibular-talar-calcaneal joints was performed, using a free graft of the autologous fibula, compression, and stabilization with a RALCA® external fixator. A pulsatile electromagnetic field was associated to accelerate bone callus formation and reduce postoperative pain. This patient was followed up for two years. Conclusions: The treatment objective was achieved by fusing the tibiotarsal joint, by starting early support and functional capacity. The results also prove the benefits of compression performed with external fixators in arthrodesis. The use of the associated electromagnetic field accelerated osteogenesis, bone consolidation and stabilization were achieved, edema and pain decreased, as well as the patient's reincorporation into society. No other similar surgical technique was found in the reviewed literature(AU)

Guía práctica para la confección del expediente de Especialista de Segundo grado / Practical Guide for Preparing the File for Second Degree Specialist

El especialista de Segundo grado es un profesional de las ciencias de la salud que demuestra un dominio de excelencia en su especialidad con alto nivel de conocimientos y competencia profesional lo que debe quedar demostrado ante un tribunal de especialización de segundo grado. En este sentido, por Acuerdo del Consejo de Estado de fecha 29 de junio de 2009 se emite la resolución 132, que aprobó el Reglamento para la obtención del Segundo grado en las ciencias de la salud, y que dispone en cuatro capítulos los siguientes aspectos: los requisitos y formalidades para la obtención del título, la tramitación de las solicitudes, la constitución y funcionamiento de los tribunales y las reclamaciones ante el viceministro para la Docencia y la Investigación en el caso de desacuerdo del aspirante con el dictamen del tribunal evaluado....

Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.

Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.

H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.

ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is particularly aggressive, with enhanced incidence of tumor relapse, resistance to chemotherapy, and metastases. As the mechanistic basis for this aggressive phenotype is unclear, treatment options are limited. Here, we showed an increased population of myeloid-derived immunosuppressor cells (MDSCs) in TNBC patients compared with non-TNBC patients. We found that high levels of the transcription factor ΔNp63 correlate with an increased number of MDSCs in basal TNBC patients, and that ΔNp63 promotes tumor growth, progression, and metastasis in human and mouse TNBC cells. Furthermore, we showed that MDSC recruitment to the primary tumor and metastatic sites occurs via direct ΔNp63-dependent activation of the chemokines CXCL2 and CCL22. CXCR2/CCR4 inhibitors reduced MDSC recruitment, angiogenesis, and metastasis, highlighting a novel treatment option for this subset of TNBC patients. Finally, we found that MDSCs secrete prometastatic factors such as MMP9 and chitinase 3-like 1 to promote TNBC cancer stem cell function, thereby identifying a nonimmunologic role for MDSCs in promoting TNBC progression. These findings identify a unique crosstalk between ΔNp63+ TNBC cells and MDSCs that promotes tumor progression and metastasis, which could be exploited in future combined immunotherapy/chemotherapy strategies for TNBC patients.

Spliceosomal DEAH-Box ATPases Remodel Pre-mRNA to Activate Alternative Splice Sites.

During pre-mRNA splicing, a central step in the expression and regulation of eukaryotic genes, the spliceosome selects splice sites for intron excision and exon ligation. In doing so, the spliceosome must distinguish optimal from suboptimal splice sites. At the catalytic stage of splicing, suboptimal splice sites are repressed by the DEAH-box ATPases Prp16 and Prp22. Here, using budding yeast, we show that these ATPases function further by enabling the spliceosome to search for and utilize alternative branch sites and 3' splice sites. The ATPases facilitate this search by remodeling the splicing substrate to disengage candidate splice sites. Our data support a mechanism involving 3' to 5' translocation of the ATPases along substrate RNA and toward a candidate site, but, surprisingly, not across the site. Thus, our data implicate DEAH-box ATPases in acting at a distance by pulling substrate RNA from the catalytic core of the spliceosome.

Single Molecule Cluster Analysis dissects splicing pathway conformational dynamics.

We report Single Molecule Cluster Analysis (SiMCAn), which utilizes hierarchical clustering of hidden Markov modeling-fitted single-molecule fluorescence resonance energy transfer (smFRET) trajectories to dissect the complex conformational dynamics of biomolecular machines. We used this method to study the conformational dynamics of a precursor mRNA during the splicing cycle as carried out by the spliceosome. By clustering common dynamic behaviors derived from selectively blocked splicing reactions, SiMCAn was able to identify the signature conformations and dynamic behaviors of multiple ATP-dependent intermediates. In addition, it identified an open conformation adopted late in splicing by a 3' splice-site mutant, invoking a mechanism for substrate proofreading. SiMCAn enables rapid interpretation of complex single-molecule behaviors and should prove useful for the comprehensive analysis of a plethora of dynamic cellular machines.

Evaluación de resultados de la osteotomía en cuña cerrada de Coventry para corregir el genus valgum / Results of Coventry closing wedge osteotomy in the correction of genu valgum

Fundamento: los pacientes con deformidad en genus valgum asociada o no a osteoartritis unicompartimental lateral, son candidatos para una osteotomía varizante del fémur distal. Objetivo: evaluar los resultados con la osteotomía en cuña cerrada del fémur distal para el genus valgum. Métodos: se realizó un estudio descriptivo prospectivo a un grupo de pacientes con el diagnóstico de genus valgum, operados con la osteotomía de Coventry MB en el Hospital Militar Universitario Octavio de la Concepción y de la Pedraja de Camagüey, desde enero de 2009 hasta diciembre de 2013 y el tiempo promedio de seguimiento de los pacientes fue de 26 meses. El universo lo conformaron 39 pacientes con el diagnóstico de genus valgum operados con la técnica de Coventry MB. La muestra no probabilística la conformaron 36 pacientes. Las variables de estudio fueron edad, sexo, tiempo de consolidación, las complicaciones, el ángulo femorotibial y la evaluación según escala evaluativa para la rodilla. Resultados: predominó el grupo de edades entre 51 y 60 años para un 50 %; el sexo más afectado fue el femenino con un 58,3 %; el tiempo de consolidación fue de 14 a 24 semanas en el 66,6 %; al finalizar el trabajo se logró un ángulo tibiofemoral promedio de 4,5 grados de valgo y la escala para la rodilla mejoró 33 puntos; los resultados de la osteotomía en cuña cerrada fueron excelentes en el 97,2 % del total de pacientes operados. Conclusiones: la osteotomía de Coventry MB demostró ser excelente para corregir el genus valgum.

Background: patients with genu valgum associated or not to lateral unicompartmental osteoarthritis are candidates for distal femoral varus osteotomy. Objective: to evaluate the results of distal femoral Coventry closing wedge osteotomy in the correction of genu valgum. Methods: a descriptive, prospective study was conducted in a group of patients with the diagnosis of genu valgum who underwent a Coventry osteotomy in Octavio de la Concepción y de la Pedraja Teaching Military Hospital, Camagüey from January 2009 to December 2013. The average time of monitoring of the patients was 26 months. The universe was composed of 39 patients with the diagnosis of genu valgum who underwent a Coventry osteotomy. The sample consisted of 36 patients. The variables of the study were the following: age, sex, knitting time, complications, femorotibial angle and the evaluation according to the evaluative scale for the knee. Results: the age group 51-60 years old predominated for a 50 %. Female was the most affected sex for a 58, 3 %. The knitting time was from 14 to 24 weeks in the 66, 6 % of the patients. At the end of the treatment, an average femorotibial angle of 4, 5 degrees was achieved and the scale for the knee improved on 33 points. The results of closing wedge osteotomy were excellent in the 97, 2 % of the patients who underwent the operation.

Las bandas de Liesegang como origen de los patrones simétricos del esmalte / Liesegang rings as origin of enamel symmetrical patterns

INTRODUCCIÓN:en los dientes existen variadas estructuras visibles que tienen formas y patrones simétricos repetitivos como los prismas, los penachos, los husillos del esmalte, las bandas de Hunter-Schreger y las líneas incrementales de Retzius. Por otro lado, los anillos de Liesegang, estudiados y aplicados desde hace más de cien años por los geólogos y otras disciplinas, son bandas simétricas repetitivas incrementales halladas en minerales naturales que se asemejan a los observados en el esmalte dental. El objetivo de este artículo es revisar los procesos, ampliamente conocidos, de formación de los anillos de Liesegang en la naturaleza y relacionarlos con la mineralización del esmalte dental y con la conformación de su anatomía característica. MÉTODOS: para este efecto se hizo una revisión bibliográfica, delimitada al período comprendido entre 1970 y 2013 en las bases de datos Science Direct, Springer, Medline y Pubmed, de donde se seleccionaron 51 referencias con información original y/o datos relevantes del tema estudiado. RESULTADOS Y CONCLUSIONES: un análisis detallado del proceso de formación de estas bandas y la similitud de los casos del mineral rocoso y del mineral dental, llevan a pensar que los procesos que se desarrollan en las rocas y en tejidos dentales duros serían los mismos.

INTRODUCTION: teeth contain various visible structures that have repeating shapes and symmetrical patterns such as prisms, crests, enamel spindles, Hunter-Schreger bands, and Retzius incremental lines. On the other hand, Liesegang rings, studied and applied for over a hundred years by geologists and other specialists, are incremental repetitive symmetrical bands found in natural minerals which are similar to those observed in tooth enamel. This article aims to review the widely known processes of formation of Liesegang rings in nature and relate them with dentin mineralization and the conformation of their characteristic anatomy. METHODS: to this end, a bibliographic review was conducted, restricted to the 1970-2013 period, in the Science Direct, Springer, Medline, and Pubmed databases, finally selecting 51 references with original information or relevant data on the subject. RESULTS AND CONCLUSIONS: a detailed analysis of the processes of formation of these rings and the similarity of rocky and dental minerals lead to think that the processes developed in rocks and hard dental tissues would be the same.

Thymopoietin Beta and Gamma Isoforms as a Potential Diagnostic Molecular Marker for Breast Cancer: Preliminary Data.

Thymopoietin (TMPO) is an inner nuclear membrane protein, the coding gene named equally, can give arise to six isoforms by alternative splicing. This gene has been found up regulated in several types of cancer. At present work, we evaluated the TMPO isoforms generated by alternative splicing as well as the protein signal detection in breast cancer samples. TMPO expression was analyzed by immunohistochemistry in tissue microarray containing 46 breast tissue samples including normal (n = 6), benign lesions (n = 18) (fibroadenomas (n = 6), fibrocystic changes (n = 6), ductal hyperplasias (n = 6)) and breast carcinoma (n = 22). Isoforms -α, -ß and -γ of TMPO were evaluated using RT-PCR; clinical-pathological correlation analysis were done by mean of X(2). Neither the normal nor the benign lesions of the breast showed positive TMPO immunodetection, whilst 45 % of the breast carcinomas were immunopositive (p = 0.000), nine of ten positives carcinomas correspond to the Luminal A subtype. Further, alpha isoform was present in all breast samples analyzed; however, beta and gamma isoforms were only present in ten (p = 0.003) and 17 (p = 0.000), respectively, in the breast cancer samples. According with the present data, we suggest that TMPOß and -γ isoforms could provide a potential reliable diagnostic marker for breast cancer.

PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.

Metastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis.

ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.

Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors.

The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.