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.

A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

Leptin and leptin receptor expression in the myometrium and uterine myomas: Is leptin involved in tumor development?

Leptin, the product of the obesity (ob) gene, along with its receptors (Ob-Rs), is expressed in several tissues and organs. Evidence has been provided that leptin, in addition to being involved in obesity development, plays a role in the regulation of the female reproductive system, angiogenesis and tumor growth. Uterine myoma is a rather common disease that develops more frequently in obese than lean women, where plasma leptin concentrations are elevated. RT-PCR and Western blotting showed that leptin was expressed, as mRNA and protein, in several uterine myomas but not in normal myometrium, while leptin receptors were expressed in both tissues. Immunocytochemistry indicated that leptin-immunoreactivity was located in both myometrial cells and blood-vessel walls of uterine myomas. Leptin(22-56), at concentrations of 10(-7) and 10(-6) M, enhanced the proliferative activity of both the normal myometrium and myoma cells in primary culture. Taken together, our findings allow us to suggest that leptin, acting through autocrine-paracrine mechanism(s), may be involved in the development of uterine myomas.

The role of botulinum toxin injection and upper esophageal sphincter myotomy in treating oropharyngeal dysphagia.

The aims of this study were to assess the efficacy and safety of botulinum toxin (BoTox) injection in the cricopharyngeus muscle (CP) and CP myotomy in patients with oropharyngeal dysphagia (OPD) and to identify factors predicting the outcome of these treatments. The study involved patients with persistent OPD despite 2-6 months of rehabilitation, who all underwent clinical evaluation, esophageal manometry, upper gastrointestinal endoscopy, and videofluoroscopy (VFS). Patients received 5-10 BoTox units injections in the CP, identified by electromyography. Surgical myotomy of the upper esophageal sphincter was performed when dysphagia persisted after two BoTox injections. After treatment, patients were reevaluated with clinical interviews and VFS. The study population included 21 patients (15 mean and 6 women; median age, 68 years), classified into three groups, based on the etiology of their OPD: eight (38%) had central nervous system abnormalities, five (24%) had peripheral nerve disease, and eight (38%) were classified as idiopathic. The median time since the onset of dysphagia was 18 months. Thirteen of 21 patients (62%) needed supplemental/total gastrostomy feeding, and 5 of 21 (24%) had tracheostomy. One patient died, on posttreatment day 7, due to massive aspiration. No other BoTox-related complications were observed. After BoTox injection, dysphagia improved in 9 of 21 (43%) patients. Severely altered VFS findings and CP incoordination or low activity predicted BoTox failure at multivariate analysis. Dysphagia improved in 8 of 11 (72.7%) patients who failed to respond to BoTox and underwent myotomy. A mild impairment of VFS findings and a higher pressure of pharyngeal contractions best predicted response to BoTox with or without myotomy. BoTox injection can be used as the first therapeutic option in patients with OPD: it is safe and simple and relieves dysphagia in 43% of cases. If BoTox fails, CP myotomy can be offered to patients with preserved oral and tongue activity at VFS and an intact bolus propulsion ability on manometry.