FOXA1 represses the molecular phenotype of basal breast cancer cells.

Breast cancer is a heterogeneous disease that comprises multiple subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is, in part, attributed to estrogen receptor (ER)-α positivity and antihormone responsiveness. Expression of the forkhead box transcription factor, FOXA1, similarly correlates with the luminal subtype and patient survival, but is also present in a subset of ER-negative tumors. FOXA1 is also consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, breast cancer cell lines representing the basal subtype do not express FOXA1. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed expression microarray analyses on FOXA1-positive and ER-positive (MCF7, T47D), or FOXA1-positive and ER-negative (MDA-MB-453, SKBR3) luminal cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Gene set enrichment analyses revealed FOXA1 silencing causes a partial transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to a subset of both luminal and basal genes within luminal breast cancer cells, and loss of FOXA1 increases enhancer RNA transcription for a representative basal gene (CD58). These data suggest FOXA1 directly represses a subset of basal signature genes. Functionally, FOXA1 silencing increases migration and invasion of luminal cancer cells, both of which are characteristics of basal subtype cells. We conclude FOXA1 controls plasticity between basal and luminal breast cancer cells, not only by inducing luminal genes but also by repressing the basal phenotype, and thus aggressiveness. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward more aggressive cancers.

Focus Issue on Squamous Cell Carcinoma: Practical Concerns Regarding the 7th Edition AJCC Staging Guidelines.

The 7th edition of the AJCC Cancer Staging Manual represents a dramatic shift in the way that cutaneous squamous cell carcinoma (cSCC) is staged, in that it is first attempt to incorporate evidence-based medicine into the staging guidelines for cSCC. In our opinion, the changes made to the seventh edition represent a significant improvement over previous editions and will ultimately lead to improved patient stratification, more accurate prognostic data, and a better framework to guide clinical decision making. However, there are a number of issues within the latest guidelines that require clarification or are impractical for clinical practice. The purpose of this paper is to highlight the key changes to the 6th edition staging manual as they pertain to cSCC, to point out impractical component of the 7th edition and/or aspects that require further clarification, and to make recommendations that address any current shortcomings to improve subsequent editions. Specific focus will be given to the inclusion of separate guidelines for cSCC and Merkel cell carcinoma (MCC), the incorporation of high-risk factors as modifiers of T stage, the addition of new guidelines for advanced T stage, and the changes in stratification of lymph node status. This paper is modified from a more comprehensive treatment of the staging of nonmelanoma skin cancer by Warner and Cockerell entitled "The new 7th edition American joint committee on cancer staging of cutaneous nonmelanoma skin cancer: a critical review," in the American Journal of Clinical Dermatology (paper accepted, pending publication).

Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology.

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.

Prevalence of cavum septum pellucidum in schizophrenia studied with MRI.

OBJECTIVE: To study the prevalence of cavum septum pellucidum (CSP), a midline developmental anomaly, in patients with schizophrenia. METHODS: Three-millimeter coronal T1 weighted MRI images of 43 normal controls and 73 patients with schizophrenia were examined. The images were resampled into 1-mm slices and CSP was measured by the number of slices in which it appeared. RESULTS: Patients had significantly higher incidence of CSP (Fisher's exact test 0.042; one-sided). Eighteen (41.9%) of the controls and 44 (60.3%) of patients had a CSP, and one of 46 controls and three of 73 patients had a large CSP of six slices or more. There was no relationship between the presence or size of CSP and regional brain volumes or volumes of hippocampus-amygdala complex, caudate, superior temporal gyrus or ventricular CSF. CONCLUSION: Higher incidence of CSP may reflect a neurodevelopmental disturbance in schizophrenia.

Quantitative anatomy of the scapula.

Thirty adult bony scapulae were used to report detailed bony dimensions of the scapula. The measurements of bony dimensions of the scapula included the glenoid, coracoid, spine, and body. The results of the measurements showed that the thickest bony stock (posteroanterior diameter), with a mean value of 13 mm to 23 mm in the glenoid process, was found in the middle third of the area within 1 cm medial to the glenoid rim. In the scapular spine region, the greatest superoinferior diameter of the bone was noted in the lateral portion of the spine, followed by the medial portion. It was also found that smallest superoinferior diameter (2 mm to 7 mm) of the spine was located at the middle portion between the base and ridge along the whole spine. On the lateral border of the scapula, the posteroanterior diameter of bone was relatively greater for the upper portion (8 mm) than for the lower portion, including the inferior angle (6 mm). This information may be helpful in open reduction and internal fixation of significantly displaced scapular fractures.