Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.
Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the ''gatekeeper'' for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMPactivated protein kinase, in the development of endometrial carcinoma. Experimental Design: We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells. Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverseTSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939. Conclusions: Inactivation ofTSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.
Despite improvements in treatment of patients with head and neck squamous cell carcinoma (HNSCC) over the last two decades, the survival rate of these patients has not increased significantly. One of the major factors in the poor outcome of the disease is regional metastasis. To better understand the mechanisms of this process at the protein level, we performed two-dimensional electrophoresis (2-DE) and mass spectrometry using SELDI ProteinChip technology to identify proteins differentially expressed in two HNSCC cell lines, UMSCC10A and UMSCC10B, from the same patient. UMSCC10A was derived from the primary tumor and UMSCC10B from a metastatic lymph node. The differentially expressed proteins were excised from the gels. Following in-gel digestion by trypsin, mass profiles of the peptides were generated. Proteins were identified by submitting the peptide mass profiles to a public available NCBInr databases (www.proteometrics.com). Two membrane-associated proteins, annexin I and annexin II and glycolytic protein enolase-alpha were found to be upregulated, and calumenin precursor down-regulated, in metastatic cell line UMSCC10B. The identity of these proteins was confirmed by analyzing additional peptide mass fingerprints obtained by endoproteinase lysine-C digestion. The results were also validated by Western blotting analysis. Our results showed that enolase-alpha, annexin-I and annexin-II might be important molecules in head and neck cancer invasion and metastasis. The results also suggest an important complementary role for proteomics in identification of molecular abnormalities important in cancer development and progression.
Antigen activation of the B-cell receptor (BCR) may play a role in the pathogenesis of human follicular lymphoma (FL) and other B-cell malignancies. However, the nature of the antigen(s) recognized by tumor BCRs has not been well studied. Here, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL immunoglobulins (Igs) recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin monoclonal antibody in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4% vs. 10%; P=0.0022). However, vimentin-reactive FL Igs did not share complimentarity determining region 3 motifs and were not homologous. Vimentin was expressed in the T-cell rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B-cell malignancies. These findings may lead to better understanding of the biology and natural history of FL and other B cell malignancies.
BackgroundThere are racial/ethnic disparities in breast cancer mortality may be attributed to differences in receipt of adjuvant cancer treatment. Our purpose was to determine whether the mortality disparities could be explained by racial/ethnic differences in long-term adherence to adjuvant endocrine therapy (AET).MethodsWe conducted a retrospective cohort study with the Texas Cancer Registry and Medicaid claims-linked dataset of women (20-64 years) diagnosed with local and regional breast cancer who filled a prescription for AET from 2000-2008. Adherence to AET was measured at three time points (1-, 3-, and 5-year adherence) using a value for the percentage of medication filled for each period divided by the total number of possible prescriptions prescribed (Medication Possession Ratio, MPR). We created a binary variable of adherence (MPR≥80%). We performed multivariable logistic regressions to assess racial differences for the odds of AET adherence and Cox proportional hazard models to determine the risk of mortality adjusting for potential confounding variables of SES, comorbidities, tumor prognostic factors, and other cancer treatment.ResultsOf the 1,497 women with breast cancer who initiated AET, 56.9%, 42.3%, and 33.3% were adherent for 1, 3, and 5-years, respectively. Hispanics compared to non-Hispanic whites did differ in the proportion that were adherent to 5-years of AET. In the adjusted analysis for long-term adherence to AET, Hispanics did not have a significantly increased risk of death compared to non-Hispanic white patients (HR: 1.13, 95% CI: 0.58-2.21). However, black compared to non-Hispanic white patients had significantly lower odds of three-year adherence (OR: 0.45, 95% CI: 0.28-0.73). After controlling for 5-year adherence to AET, the risk of death for black compared to non-Hispanic white patients was 12% lower (HR: 1.90; 95% CI: 1.03-3.51) and in the fully adjusted model, the disparity was reduced and no longer significant (OR: 1.86, 95% CI: 0.94-3.66).ConclusionsLong-term adherence in the Medicaid population is suboptimal and racial/ethnic differences in AET adherence may partially explain disparities in mortality. This study underscores the critical need to ensure long-term adherence to AET for all racial/ethnic groups to decrease disparities in mortality.
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