EZH2 promotes a bi-lineage identity in basal-like breast cancer cells.

The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a 'bi-lineage' differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony-formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.

Wwox inactivation enhances mammary tumorigenesis.

Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3-4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (Wwox(C3H)+/-) and incidence of mammary tumor formation was evaluated. Although 50% of the female Wwox(C3H)+/- mice developed mammary carcinomas, only 7% of Wwox(C3H)+/+ mice did. Intriguingly, mammary tumors in Wwox(C3H)+/- mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-α (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorage-independent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in Wwox(C3H)+/- mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.

Heparanase expression: a potential ancillary diagnostic tool for distinguishing between malignant cells and reactive mesothelium in body cavity effusions.

OBJECTIVE: Heparanase, an endoglycosidase that cleaves heparan sulphate, is frequently expressed in carcinomas and was suggested to play a role in cell invasion and metastasis. We investigated whether heparanase expression may serve as a reliable marker to discriminate benign mesothelial cells from malignant cells shed into body cavities. METHODS AND RESULTS: Cytological smears of effusions from 51 hospitalized patients were immunostained for heparanase. Strong immunoreactivity was noted in 35 of 40 (88%) carcinoma samples and in all three malignant mesothelioma cases. Only rare (<3%) reactive mesothelial cells were noted showing a faint negligible staining. Specificity was 100%, sensitivity 88%, and positive and negative predictive values were 100% and 89% respectively. CONCLUSIONS: Our results suggest that heparanase may be of value as a complementary component in a diagnostic panel of markers, contributing to its reliability and accuracy.

Nodular fasciitis of the breast: report of a case initially diagnosed by fine needle aspiration cytology.

BACKGROUND: Nodular fasciitis is a rare benign pseudosarcomatous proliferation of fibroblasts in the breast, in which the clinical examination and mammographic findings may closely mimic mammary carcinoma. CASE: A case of nodular fasciitis was diagnosed by fine needle aspiration. A 15-year-old girl was admitted to our hospital with a recently noticed, rapidly growing mass in the right breast. The aspirate contained cohesive groups of fusiform cells with elongated and oval nuclei, regular nuclear membranes and inconspicuous nucleoli, intermingled with scattered lymphocytes, red blood cells and characteristic granular background substance. A cytologic diagnosis of nodular fasciitis was made and confirmed histologically. CONCLUSION: Mammary nodular fasciitis is often clinically suspicious for carcinoma and rarely diagnosed by fine needle aspiration cytology. A literature search yielded only five reported cases. The cytologic diagnosis of this entity helps to choose the correct surgical procedure, preventing psychological trauma to the patient.

Physician unwitting participation in abuse and neglect of persons with developmental disabilities.

The vast majority of birth parents and foster parents for children with special needs do the best they can in challenging circumstances. Many describe the frustrating circumstance of knowing more than their physicians about their child's unusual medical conditions. In general, physicians are well-advised to listen carefully to the reports of observant, caring parents and foster parents, and to give these observations at least as much weight as their own. However, in the work of our traveling clinic we have observed a number of situations of abuse and neglect which were perpetrated by parents or foster parents, and where the actual acts of abuse and/or neglect were wholly or in part endorsed, in writing, by the treating physician.

Myoblastomatoid carcinoma of the breast: an unusual variant of apocrine carcinoma: report of a case with fine-needle aspiration cytology and immunohistochemical study.

Fine-needle aspiration cytology, immunohistochemistry, and histopathologic findings are described in a case of myoblastomatoid carcinoma of the breast. The aspirate contained many small and large clusters of cohesive atypical cells with abundant foamy-to-granular cytoplasm and nuclei that show moderate pleomorphism. These tumors can be easily misinterpreted as either fibrohistiocytic or myoblastomatoid (granular cell) tumors, and by using immunohistochemical stains, the epithelial origin can be elucidated. This case report provides the first description of the fine-needle aspiration cytomorphology of this distinctive variant of apocrine carcinoma.

Collecting duct carcinoma of kidney: a cytological study and case report.

An intraoperative cytological imprint of a well study case of collecting duct carcinoma of the kidney is reported. Papillary structures, fibrotic desmoplastic stroma, tubular formations, and tumoral cells with high grade cytological atypia were found. Cytological details described help to avoid misinterpretation of collecting duct carcinoma as a metastatic tumor. The peculiar morphology, the immunohistochemical and biological behavior of this rare tumor justifies its classification in a special group.

Pain rehabilitation. 3. Cancer pain, pelvic pain, and age-related considerations.

This self-directed learning module highlights assessment and therapeutic options in the management of cancer pain, pelvic pain, and the pain problems of the elderly and children. It is part of the chapter on pain rehabilitation in the Self-Directed Medical Knowledge Program for practitioners and trainees in physical medicine and rehabilitation. This article delineates causes of cancer pain, discusses strategies for approaching each specialized population, and provides specific clinical examples to illustrate management issues, with emphasis on prevention. New advances include understanding the pain experience in children and elderly adults; investigation of psychosocial aspects of pelvic pain; and use of patient-controlled analgesia, opioids, and multimodality techniques for acute, perioperative, and chronic pain in these age groups.

Rehabilitation principles in the care of gynecologic and obstetric patients.

Literature examining disabilities and rehabilitation in gynecologic and obstetric patients is limited. Among the musculoskeletal, vascular, neurologic, hormonal, and sexual problems described, pelvic floor laxity is the etiology for several dysfunctional states and is common to both parous and nonparous women. The focus of this paper is on one of the dysfunctional states--urinary stress incontinence--which in previous work had a reported incidence of 30% of all women and may affect up to 63% of postmenopausal women. This study, applying rehabilitation principles to diagnosis and treatment, found the incidence of stress incontinence to be 20 to 30% of women, pregnant or not, who did no specific pelvic floor exercise. A group of women, not pregnant, who did Kegel exercises for pelvic floor strengthening had only a 6% incidence of stress incontinence. There is a need to determine whether pelvic floor exercise, done effectively, could minimize this problem in postmenopausal women. Rehabilitation principles may be applied to the diagnosis and treatment of other disabling conditions in gynecology and obstetrics.

Teaching doctors to treat doctors: medical student peer counselling.

Physicians' emotional problems need to be recognized and treated. Intervention and prevention in this problem area have been attempted at the Medical College of Wisconsin through a programme of peer counselling designed to teach student physicians how to recognize and treat emotional difficulties faced by their peers. During the 18 months that the programme has been in operation, 20 peer counsellors reported a total 1,185 hours spent in counselling their peers, lending credence to the speculation that doctors will turn to their peers for help if, in medical school, there is acceptance of fallibility and responsiveness on the part of peers.