PYGOPUS2 expression in prostatic adenocarcinoma is a potential risk stratification marker for PSA progression following radical prostatectomy.

AIMS: Prostate cancer (PrCa) is the most frequently diagnosed non-cutaneous cancer in men. Without clear pathological indicators of disease trajectory at diagnosis, management of PrCa is challenging, given its wide-ranging manifestation from indolent to highly aggressive disease. This study examines the role in PrCa of the Pygopus (PYGO)2 chromatin effector protein as a risk stratification marker in PrCa. METHODS: RNA expression was performed in PrCa cell lines using Northern and RT-PCR analyses. Protein levels were assessed using immunoblot and immunofluorescence. Immunohistochemistry was performed on tissue microarrays constructed from radical prostatectomies with 5-year patient follow-up data including Gleason score tumour staging, margin and lymph node involvement and prostate serum antigen (PSA) levels. Biochemical recurrence (BR) was defined as a postoperative PSA level of >0.2 nL. Univariate and multivariate analyses were performed using SAS and Kaplan-Meier curves using graphPad (Prism). RESULTS: In vitro depletion of PYGO2 by RNAi in both androgen receptor positive and negative PrCa cell lines attenuated growth and reduced Ki67 and 47S rRNA expression, while PYGO2 protein was localised to the nuclei of tumours as determined by immunohistochemistry. High expression levels of PYGO2 in tumours (n=156) were correlated with BR identified as PSA progression, after 7-year follow-up independent of other traditional risk factors. Most importantly, high PYGO2 levels in intermediate grade tumours suggested increased risk of recurrence over those with negative or weak expression. CONCLUSION: Our data suggest that elevated PYGO2 expression in primary prostate adenocarcinoma is a potential risk factor for BR.

Selective estrogen receptor modulators and betulinic acid act synergistically to target ERα and SP1 transcription factor dependent Pygopus expression in breast cancer.

AIMS: Estrogen and progesterone hormone receptor (ER and PR) expression in invasive breast cancer predicts response to hormone disruptive therapy. Pygopus2 (hPYGO2) encodes a chromatin remodelling protein important for breast cancer growth and cell cycle progression. The aims of this study were to determine the mechanism of expression of hPYGO2 in breast cancer and to examine how this expression is affected therapeutically. METHODS: hPYGO2 and ER protein expression was examined in a breast tumour microarray by immunohistochemistry. hPYGO2 RNA and protein expression was examined in ER+ and ER- breast cancer cell lines in the presence of selective estrogen hormone receptor modulator drugs and the specificity protein-1 (SP1) inhibitor, betulinic acid (BA). The effects of these drugs on the ability for ER and SP1 to bind the hPYGO2 promoter and affect cell cycle progression were studied using chromatin immunoprecipitation assays. RESULTS: hPYGO2 was expressed in seven of eight lines and in nuclei of 98% of 65 breast tumours, including 3 Ductal carcinoma in situ and 62 invasive specimens representing ER-negative (22%) and ER-positive (78%) cases. Treatment with either 4-Hydroxytamoxifen (OHT) or fulvestrant reduced hPYGO2 mRNA 10-fold and protein 5-10-fold within 4 h. Promoter analysis indicated an ER/SP1 binding site at nt -225 to -531 of hPYGO2. SP1 RNA interference and BA reduced hPYGO2 protein and RNA expression by fivefold in both ER- and ER+ cells. Further attenuation was achieved by combining BA and 4-OHT resulting in eightfold reduction in cell growth. CONCLUSIONS: Our findings reveal a mechanistic link between hormone signalling and the growth transcriptional programme. The activation of its expression by ERα and/or SP1 suggests hPYGO2 as a theranostic target for hormone therapy responsive and refractory breast cancer.

Evaluation of cell-line-derived xenograft tumours as controls for immunohistochemical testing for ER and PR.

Quality control (QC) for immunohistochemistry (IHC) analysis routinely incorporates archived specimens for on-slide control material. We have assessed the utility of cell-line-derived xenograft (CDX) tumours for QC in breast estrogen receptor (ER) and progesterone receptor (PR) biomarker testing. Immunoblot and IHC analyses were used to select cell lines with different steady-state levels of ER and PR expression. CDX tumours all demonstrated consistent and comparable expression of ER and PR with corresponding cell lines from which they were derived. Three pathologists experienced in breast biomarker reporting scored tumours from different locations on mammary fat pads to determine reproducibility. Tumours from different locations were consistently scored as identical, and the CDX tumours representing different levels of biomarker expression were similar to patient-derived controls. Pathologists could not consistently distinguish CDX tumours from patient-derived controls, suggesting that within the appropriate quality management setting, CDX tumours may serve as control material for reporting purposes.

Utilidad de la resonancia magnética nuclear en el diagnóstico de la extensión del micetoma / Use of magnetic nuclear resonance in the diagnosis of spreading in mycetoma

Comunicamos un caso de micetoma causado por Actinomadura madurae con el hallazgo de los granos en la biopsia de piel y desarrollo del agente etiológico por cultivo del material obtenido por biopsia quirúrgica. Destacamos la utilidad de la resonancia magnética nuclear en la evaluación previa al acto quirúrgico, especialmente en cuanto al compromiso osteoarticular (AU)

Utilidad de la resonancia magnética nuclear en el diagnóstico de la extensión del micetoma / Use of magnetic nuclear resonance in the diagnosis of spreading in mycetoma

Comunicamos un caso de micetoma causado por Actinomadura madurae con el hallazgo de los granos en la biopsia de piel y desarrollo del agente etiológico por cultivo del material obtenido por biopsia quirúrgica. Destacamos la utilidad de la resonancia magnética nuclear en la evaluación previa al acto quirúrgico, especialmente en cuanto al compromiso osteoarticular

Neurofibromatosis segmentaria / Segmentary neurofibromatosis

Comunicamos un caso de neurofibromatosis segmentaria en un paciente de sexo masculino de 65 años de edad. Los neurofibromas se ubicaban en la región escapular derecha. La evolución de los mismos es de cinco años. No fueron constatadas manchas café con leche ni otra alteración característica de la neurofibromatosis tipo 1. En nuestro caso el principal diagnóstico diferencial fue con acrocordones-nevos fibromatosos. Efectuamos una breve revisión de la literatura (AU)

Neurofibromatosis segmentaria / Segmentary neurofibromatosis

Comunicamos un caso de neurofibromatosis segmentaria en un paciente de sexo masculino de 65 años de edad. Los neurofibromas se ubicaban en la región escapular derecha. La evolución de los mismos es de cinco años. No fueron constatadas manchas café con leche ni otra alteración característica de la neurofibromatosis tipo 1. En nuestro caso el principal diagnóstico diferencial fue con acrocordones-nevos fibromatosos. Efectuamos una breve revisión de la literatura