TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP.

Objective To examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin-containing intrauterine device (IUD). A molecular signature of treatment failure is proposed. Methods A retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR. Results The mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non-nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy. Conclusions FOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD.

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The implementation and enforcement of the College of American Pathologists Survey Checklist ANP 22432 has renewed attention on the issue of outdating of antibodies used for immunohistochemical analysis. The current study examined the staining patterns of 26 recently acquired primary antibodies and their expired counterparts. Two reviewers examined sequential sections of formalin-fixed, paraffin-embedded tissue samples for staining intensity and percentage of positivity. Appropriate positive and negative control studies were performed. Of the 26 antibodies, 20 exhibited no difference in percentage of positivity or staining intensity. Of the remaining 6, 3 showed better performance with the expired cohort and 3 with nonexpired antibodies. However, no antibody staining characteristics varied by more than 1 step, and in no case was positive staining lost after antibody expiration. Negligible differences exist in immunostaining between outdated and current antibodies. Thus, exemption for primary antibodies from existing regulations would conserve resources without adversely impacting patient care.

The most common genetic and molecular process leading to sporadic colorectal cancer is chromosomal instability. By contrast, mismatch repair deficiency, which results in high levels of microsatellite instability or lack of mismatch repair (MMR) protein expression on immunohistochemistry (IHC), is the predominant cancer pathway in patients with Lynch syndrome (LS). Importantly, patients with LS may still develop sporadic tumors through chromosomal instability. Testing tumors with IHC staining helps expand the spectrum of LS-related tumors. In this series, we describe 4 cancers in patients with LS that are not typical of the syndrome. Lack of MMR protein expression on IHC staining confirmed that 2 cancers are related to LS, expanding the spectrum of LS-related tumors, and the presence of MMR protein expression on IHC in the other 2 cases confirmed that they were sporadic and not related to mismatch repair deficiency and, thus, not related to LS.