Post-traumatic aneurysmal rupture involving the circle of Willis affected by fibromuscular dysplasia. A case report and systematic review.

The fatal rupture of a saccular aneurysm at the junction between the left anterior cerebral artery and anterior communicating artery affected by fibromuscular dysplasia (FMD) is a rare condition. Here is reported the case of a subject involved in a road traffic accident a few minutes before the death, which opened the debate on the real cause of death in a forensic setting. By autopsy, the examination of the brain revealed subarachnoid haemorrhage with flooding of the ventricles due to the breached saccular aneurysm of the junction between the left anterior cerebral artery and anterior communicating artery, in FMD mainly affecting the circle of Willis arteries. A spontaneous aneurysmal rupture was excluded on the basis of probabilistic analysis, in the presence of alternative hypotheses that could explain the facts. The passenger's delayed loss of consciousness may be explained as much by a hypertension-linked rupture of the aneurysm triggered by the emotional stress experienced, as by the traumatic shaking/impact of the aneurysm against the bony skull structures, in a subject predisposed to aneurysm frailty due to FMD. Overall, the concausal role of both the road traffic accident, typified by high kinetic energy, and the presence of a pre-existing aneurysmatic weakness due to FMD is fully recognized. The identification of anatomical variants, jointly with uncommon diseases at the examination of the brain base arteries in any case of isolated basal subarachnoid haemorrhage, may avoid wrong legal consequences even when the cause of death seems to be obviously of simple traumatic origin.

PKH26 staining defines distinct subsets of normal human colon epithelial cells at different maturation stages.

BACKGROUND AND AIM: Colon crypts are characterized by a hierarchy of cells distributed along the crypt axis. Aim of this paper was to develop an in vitro system for separation of epithelial cell subsets in different maturation stages from normal human colon. METHODOLOGY AND MAJOR FINDINGS: Dissociated colonic epithelial cells were stained with PKH26, which allows identification of distinct populations based on their proliferation rate, and cultured in vitro in the absence of serum. The cytofluorimetric expression of CK20, Msi-1 and Lgr5 was studied. The mRNA levels of several stemness-associated genes were also compared in cultured cell populations and in three colon crypt populations isolated by microdissection. A PKH(pos) population survived in culture and formed spheroids; this population included subsets with slow (PKH(high)) and rapid (PKH(low)) replicative rates. Molecular analysis revealed higher mRNA levels of both Msi-1 and Lgr-5 in PKH(high) cells; by cytofluorimetric analysis, Msi-1(+)/Lgr5(+) cells were only found within PKH(high) cells, whereas Msi-1(+)/Lgr5(-) cells were also observed in the PKH(low) population. As judged by qRT-PCR analysis, the expression of several stemness-associated markers (Bmi-1, EphB2, EpCAM, ALDH1) was highly enriched in Msi-1(+)/Lgr5(+) cells. While CK20 expression was mainly found in PKH(low) and PKH(neg) cells, a small PKH(high) subset co-expressed both CK20 and Msi-1, but not Lgr5; cells with these properties also expressed Mucin, and could be identified in vivo in colon crypts. These results mirrored those found in cells isolated from different crypt portions by microdissection, and based on proliferation rates and marker expression they allowed to define several subsets at different maturation stages: PKH(high)/Lgr5(+)/Msi-1(+)/CK20(-), PKH(high)/Lgr5(-)/Msi-1(+)/CK20(+), PKH(low)/Lgr5(-)/Msi-1(+)/Ck20(-), and PKH(low)/Lgr5(-)/Msi-1(-)/CK20(+) cells. CONCLUSIONS: Our data show the possibility of deriving in vitro, without any selection strategy, several distinct cell subsets of human colon epithelial cells, which recapitulate the phenotypic and molecular profile of cells in a discrete crypt location.

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.

The anatomical school of Padua.

The University of Padua is one of the most ancient in the world, being founded in 1222, and the most important anatomists of the XVI, XVII, and XVIII centuries studied and taught here. Probably, the first professor of anatomy and surgery was Bruno da Longobucco (c. 1200-c. 1286), who had previously studied at the Salerno School of Medicine. While professor in Padua, Andreas Vesalius (1514-1564) published De Humani Corporis Fabrica (1543), which is considered as the birth of the modern anatomy. Following professors were Realdo Colombo (c. 1516-1559), Gabriel Fallopius (1523-1562), Hieronymus Fabricius ab Aquapendente (1533-1619), Iulius Casserius (1552-1616), Johann Wesling (1598-1649), and Johann Georg Wirsung (1589-1643). Many other foreign scholars studied in the University of Padua, such as Thomas Linacre (c. 1460-1524), the founder of the Royal College of Physicians, Werner Rolfinck (1599-1673), and Olof Rudbeck (1630-1702), who created anatomical theatres in Germany and Sweden, respectively, on the basis of the Paduan model. The anatomy of the XVII century characteristically widened the scope of its enquiry to function, as in the Exercitatio Anatomica De Motu Cordis et Sanguinis in Animalibus (1628) by William Harvey (1578-1657). Further evolution was then given by the anatomy in the XVIII century, which tried to correlate alterations of structure with clinical symptoms. The most important anatomist of this century is Giovanni Battista Morgagni (1682-1771), whose masterpiece De Sedibus et Causis Morborum per Anatomen Indagatis (1761) is a landmark contribution that is viewed as the beginning of modern pathologic anatomy. This year falls the 300th anniversary of Morgagni's inaugural lecture on medical education, Nova Institutionum Medicarum Idea (1712), which is still relevant in its effort to stress the importance of a deep knowledge of all the preclinical and clinical aspects of medical science.

Quality management of Body Donation Program at the University of Padova.

Quality management improvement has become a recent focus of attention in medical education. The program for the donation of bodies and body parts (Body Donation Program) at the University of Padova has recently been subjected to a global quality management standard, the ISO 9001:2008 certification. The aim of the present work is to show how the above standard is useful in enhancing the efficiency of body donation procedures and the quality and output of medical education. The program is managed by means of the following interlinked procedures: the collection of body donations, death certificates, data, and body parts from living donors; the transportation and identification of cadavers; the management of bodies, body parts, equipment, instruments, purchasing of necessary materials, and setting up anatomical training sessions; the management of preventive and corrective actions; the management of documents and registration; the management of internal and external quality audits; and the review of outcomes and improvement planning. Monitoring indicators are identified in the numbers of donors and of donated body parts per year, education sessions, and satisfaction of learners and donors, as evaluated by questionnaires. The process management approach, the integrated involvement of medical, technical, and administrative staff in defining procedures, and the application of monitoring indicators allow quality improvement in all aspects of the Body Donation Program.

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.

DNA copy number profile discriminates between esophageal adenocarcinoma and squamous cell carcinoma and represents an independent prognostic parameter in esophageal adenocarcinoma.

We report multiplex ligation-dependent probe amplification analysis (MLPA) of DNA copy number alterations in 59 esophageal cancer samples, stratified by histotype. Results showed that squamous cell carcinoma (SCC) samples present clustered abnormalities with several genes altered at high frequency. Instead, esophageal adenocarcinoma (ADC) samples are characterized by a more widespread genomic instability, and in these patients total DNA copy number alterations resulted to be an independent prognostic factor. The detection of characteristic molecular changes represents a step towards a better understanding of the molecular basis of esophageal tumorigenesis, and might offer the potential for the discovery of tumor-specific biomarkers.

Body parts removed during surgery: a useful training source.

Current undergraduate medical curricula provides relatively little time for cadaver dissection. The Department of Human Anatomy and Physiology at the University of Padova has organized a pilot project with the University Hospital for the donation of body parts that are surgically removed for therapeutic purposes and destined under Italian law for destruction. The aim of the project is to improve residents' practical training skills. A survey over the last two years has shown that about 60 body parts were available each year. These included 13 upper limbs or their parts (i.e., forearm with hand, hand, and fingers) and 47 lower limbs or their parts (i.e., legs with feet, feet, or toes). The residents explained the aim of the project to potential donors, and, if patients were willing to donate, their informed consent was obtained. The residents were present in the operating theater during the surgical procedure. In the post-operative phase, the same residents performed dissections on the body part(s), following a teaching schedule prepared by a clinical anatomist, who also assisted residents during their studies. Residents also acted as tutors for undergraduate medical students who attended these dissections. The underlying pathology for which the body part was removed was examined, and surgical procedures were practiced on the body part itself. Our project provided an opportunity for a close relationship between anatomists and surgeons, reinforcing core knowledge of anatomy by appreciation of its clinical importance. The active involvement of residents as learners and as teachers in the various steps of this project improved their knowledge of surgical techniques and helped to establish a sense of ethical responsibility and respect for the human body. This approach involves study of anatomical structures from new perspectives and leads to improved surgical practice.

Surgical anatomy of the sacral hiatus for caudal access to the spinal canal.

The sacral hiatus is used for access to the spinal canal in many neurosurgical and anesthesiologic procedures. The aim of the present paper is to give a review of its anatomical characteristics relevant to permit correct and uncomplicated accesses. The sacral hiatus is posteriorly closed by the superficial dorsal sacrococcygeal ligament (also called sacrococcygeal membrane) which has to be pierced in order to gain the sacral canal. The mean distance between the hiatal apex and the dural sac has been reported to be 45-60.5 mm in adults and 31.4 mm in children. The mean sacral space depth has been observed to be 4.6 mm in adults and 3.5 mm in infants. On the basis of anatomical measurements of the sacral hiatus, lower insertion angles have been suggested in infant with respect to adult subjects (21° vs. 58°).

Vulvar cancer: prognostic factors.

BACKGROUND: Prognostic factors such as surgery and pathology in vulvar squamous cell carcinoma are studied. PATIENTS AND METHODS: 47 patients with vulva squamous cell carcinoma treated at the Gynecology Department of the University of Padua, have been retrospectively studied. RESULTS: At the univariate relapse-free survival analysis, a significant association was found for histological grade, stage of disease and type of surgery. All patients presented vulvar squamous cell carcinoma: G(1) in 25 (53%), G(2) in 14 (30%), and G(3) in 8 (17%) patients. The distribution of stages was as following: stage 1 in 6 (13%), stage 2 in 20 (43%), stage 3 in 11 (23%), and stage 4 in 10 patients (21%). Radiotherapy was performed in 13 patients. Among the 47 patients evaluable: 26 (55.3%) developed local recurrence, 12 of these patients developed a second local relapse, 3 of these also had distant metastases (lung in 1 patient, lomboaortic and mediastinic lymph nodes in the other 2 patients). Stromal invasions were 9 mm in 30 patients with 27 relapses (univariated analysis p=0 0066). Five episodes (10,6%) of thrombosis were observed. CONCLUSION: After multivariate analysis, surgery, stage and stromal invasion over 9 mm (hazard ratio=3.1; 95% confidence interval: 1.3-7.7) proved to be the most dominant predictor for relapse-free survival. Histological grades 1 and 2 were predictive of better disease-free survival (p=0.0012).

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.

Caustic ingestion and oesophageal cancer: intra- and peri-tumoral fibrosis is associated with a better prognosis.

OBJECTIVE: Oesophageal carcinoma is a well-known late complication of caustic ingestion, occurring in up to 7% of cases. We report a large series of patients with oesophageal scar cancer (SC), investigating the association between fibrosis and survival. METHODS: A total of 25 patients with a history of oesophageal SC (1979-2005) were retrospectively studied. The amount of intra- and peri-tumoral fibrotic tissue was measured with Azan-Mallory staining. A control group of patients with non-SC was used for comparison. RESULTS: Twenty-five patients (16 males:9 females, median age 59 years), presented with SC. The histotype was squamous cell carcinoma (SCC) in 20 (80%) patients, adenocarcinoma (AC) in three (12%) and verrucous carcinoma in two (8%). Oesophageal resection was performed in 17 of 25 (68%) patients; in eight (32%), only a palliative treatment (endoscopic/surgical) was possible. Mortality and morbidity rates were 4% and 40%, respectively. One-, 3- and 5-year overall actuarial survival rates for SC patients were 72%, 56% and 52%, respectively. The amount of fibrotic tissue around/within the tumour was significantly higher in SC patients (34.5% vs 5.9% non-SC, p=0.01); these patients had also a higher prevalence of tumours limited to the muscular wall (pT1-T2) (76% vs 28% non-SC, p<0.0001) and less lymph node metastases in T1-T2 cases (8% vs 34% non-SC, p=0.07). The 5-year survival was significantly better in SC patients: 71% versus 24% for resected cancers (p<0.0001), and 52% versus 15% for all observed patients (p=0.0001). CONCLUSIONS: The presence of fibrotic tissue around/within the tumour is associated with a better prognosis in SC. Fibrosis might offer a protection against both local spread and nodal dissemination.

The ankle retinacula: morphological evidence of the proprioceptive role of the fascial system.

STUDY DESIGN: Research report. OBJECTIVES: To evaluate the anatomical characteristics of the ankle retinacula and their relationship with the fasciae and muscles in healthy subjects and in patients with ankle sprain outcomes. BACKGROUND: The role of the retinacula in proprioception has begun to emerge, but without clear anatomical bases or descriptions of their possible damage in patients with ankle sprain outcomes. METHODS: Dissection, histological and immunohistochemical analysis of 27 legs. An in vivo radiological study by MRI was also performed on 7 healthy volunteers, 17 patients with outcomes of ankle sprain, and 3 amputated legs. RESULTS: The retinacula are thickenings of the deep fascia presenting bone or muscular connections. They are formed of 2-3 layers of parallel collagen fibre bundles, densely packaged with a little loose connective tissue, without elastic fibres but many nervous fibres and corpuscles. By MRI, the retinacula appeared as low-signal-intensity bands with a mean thickness of 1 mm. In patients with outcomes of ankle sprain, MR findings were abnormal retinacula thickness, signal intensity, and full-thickness gap. DISCUSSION: The retinacula are not static structures for joint stabilisation, like the ligaments, but a specialisation of the fascia for local spatial proprioception of the movements of foot and ankle. Their anatomical variations and accessory bundles may be viewed as morphological evidence of the integrative role of the fascial system in peripheral control of articular motility.

Expression and distribution of galanin receptor subtypes in the rat carotid body.

Galanin is a 29 amino acid neuropeptide that is widely distributed in the nervous system and acts by binding to three G protein-coupled receptors (GalR1, GalR2 and GalR3). In the literature, the presence of galanin has been reported in nerve fibers innervating the rat carotid body; however, direct evidence of the different galanin receptor subtypes expressed in carotid body cells has yet to be provided. In the present study, we investigated the presence and location of the three galanin receptor subtypes in 12 rat carotid bodies through real-time polymerase chain reaction (PCR) and immunohistochemistry. Real-time PCR identified GalR1 and GalR2 mRNA, with GalR2 gene expression being 100 times higher than that of the GalR1 gene. GalR3 mRNA was not detected. Statistically significant differences were not observed between the mean number of GalR1- and GalR2-positive type I cells (40.5±15.5 vs. 37.1±13.2%). Anti-GalR3 immunohistochemistry did not identify positive cells in the carotid body. Type II cells were negative for the three galanin receptor subtypes. Our findings suggest that galanin may play a neuromodulator or trophic role in type I cells by binding to GalR1 and GalR2.

Histotopographic study of the fibroadipose connective cheek system.

The purpose of this study was to investigate the morphology of the superficial musculoaponeurotic system (SMAS). Eight embalmed cadavers were analyzed: one side of the face was macroscopically dissected; on the other side, full-thickness samples of the parotid, zygomatic, nasolabial fold and buccal regions were taken. In all specimens, a laminar connective tissue layer (SMAS) bounding two different fibroadipose connective layers was identified. The superficial fibroadipose layer presented vertically oriented fibrous septa, connecting the dermis with the superficial aspect of the SMAS. In the deep fibroadipose connective layer, the fibrous septa were obliquely oriented, connecting the deep aspect of the SMAS to the parotid-masseteric fascia. This basic arrangement shows progressive thinning of the SMAS from the preauricular district to the nasolabial fold (p < 0.05). In the parotid region, the mean thicknesses of the superficial and deep fibroadipose connective tissues were 1.63 and 0.8 mm, respectively, whereas in the region of the nasolabial fold the superficial layer is not recognizable and the mean thickness of the deep fibroadipose connective layer was 2.9 mm. The connective subcutaneous tissue of the face forms a three-dimensional network connecting the SMAS to the dermis and deep muscles. These connective laminae connect adipose lobules of various sizes within the superficial and deep fibroadipose tissues, creating a three-dimensional network which modulates transmission of muscle contractions to the skin. Changes in the quantitative and qualitative characteristics of the fibroadipose connective system, reducing its viscoelastic properties, may contribute to ptosis of facial soft tissues during aging.

Extracellular signal-regulated kinase and phosphatidylinositol-3-kinase/AKT signalling pathways in the human carotid body and peripheral ganglia.

Extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/AKT signalling pathways are involved in various cell functions, but their developmental regulation in the carotid body and peripheral ganglia has not yet been fully investigated. ERK and AKT immunolocalisation and activation were studied by anti-ERK, -pERK, -AKT and -pAKT immunohistochemistry in carotid bodies and peripheral (sympathetic and sensory) ganglia, sampled at autopsy from 4 foetuses (mean gestational age 177 days), 8 infants (mean age 10 months), 8 young adults (mean age 38 years) and 6 aged adults (mean age 72.4 years). ERK and AKT immunopositivity and activation were demonstrated in both glomic type I cells and peripheral ganglionic cells and are ascribed to local action by neuromodulators or neurotrophic factors. Mean percentages of ERK- and pERK-immunopositive glomic type I cells were lower in foetuses than in infants and young adults, and those of AKT-immunopositive glomic type I cells were lower in foetuses than in young and old adults, suggesting incomplete maturation of these two signalling pathways in foetal life. Both pERK and pAKT immunoreactions were detected only in post-natal sympathetic and sensory ganglia, demonstrating that, also in peripheral ganglia, these pathways are not yet fully operative during the foetal stage.

Family history of cancer rather than p53 status predicts efficacy of pegylated liposomal doxorubicin and oxaliplatin in relapsed ovarian cancer.

BACKGROUND: The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations. METHODS: Seventy-two women received a median of 7.5 courses of PLD at 30 to 35 mg/m2 plus oxaliplatin at 70 mg/m2, and associations between BRCA1/2 and TP53 status and overall survival (OS) were determined. Thirty-eight had a short platinum-free interval (PFI; <12 months), and 34 had a long PFI (> or =12 months). RESULTS: Nine patients had BRCA1 mutations, and 1 had a BRCA2 mutation. Platinum sensitivity was associated with OS (P = 0.0001). At a median follow-up of 9.3 months, objective response rate, median time to progression, and OS were 47.3%, 5.8 months, and 12.9 months, respectively, in short PFI compared with the 76.5%, 11.5 months, and 47.7 months in long PFI. p53 status did not correlate to these parameters. The median time to progression was 11.5 months for high-risk patients versus 6.5 months for patients with sporadic cancer (P = 0.0188), and the median OS from the start of treatment was 48.7 and 16.2 months (P = 0.0032), respectively. Toxicity was mostly grade 1 or 2. CONCLUSIONS: High response rates in the long-PFI patients indicate that this treatment is beneficial and well tolerated. Platinum sensitivity and positive family history and/or a BRCA1/BRCA2 mutation are a useful predictor of response.

Morphometric analysis of infant and adult medullary nuclei through optical disector method.

In the literature, comprehensive and comparative morphometric studies of infant and adult medullary nuclei performed with unbiased methods are still lacking. In this study, the unbiased quantitative method of the optical disector was applied to analyze neuronal densities, nuclear volumes, and total neuron numbers of the hypoglossal nucleus (XII), dorsal motor nucleus of the vagus (DMNV), nucleus tractus solitarii (NTS), medial vestibular nucleus (MedVe), cuneate nucleus (Cu), nucleus of the spinal trigeminal tract, principal inferior olivary nucleus (PION), medial inferior olivary nucleus (MION), and dorsal inferior olivary nucleus (DION) in adults (16 male, six female; mean age: 37 years) and infants (five male, five female; mean age: 5 months). In both infants and adults, higher neuronal densities were found in the more ventrally located nuclei of the spinal trigeminal tract (mean values (coefficient of variation): 20,947 (0.29) and 8,990 (0.18) neurons/mm(3), respectively) and inferior olivary complex (PION: 20,010 (0.15) and 9,076 (0.10); MION: 18,667 (0.20) and 9,989 (0.13); DION: 22,424 (0.17) and 10,986 (0.20), respectively) than in the nuclei of the medullary tegmentum, that is, XII (2,747 (0.39) and 1,026 (0.31)), DMNV (2,876 (0.19) and 1,553 (0.26)), NTS (7,993 (0.17) and 2,877 (0.13)), MedVe (7,010 (0.17) and 2,918 (0.12)), and Cu (2,563 (0.23) and 1,038 (0.16)). All the medullary nuclei showed higher volumes and lower neuronal densities in adults than in infants, without statistically significant differences in total neuron numbers, probably because of postnatal development of the neuropil and microvascularization.

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.