Introduction: Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. Tumor specific expression of QSOX1 has been reported for numerous tumor types. In this study, we investigate QSOX1 as a marker of breast tumor progression and evaluate the role of QSOX1 as it relates to breast tumor growth and metastasis. Methods: Correlation of QSOX1 expression with breast tumor grade, subtype and estrogen receptor (ER) status was gathered through informatic analysis using the "Gene expression based Outcome for Breast cancer Online" (GOBO) web-based tool. Expression of QSOX1 protein in breast tumors tissue microarray (TMA) and in a panel of breast cancer cell lines was used to confirm our informatics analysis. To investigate malignant cell mechanisms for which QSOX1 might play a key role, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in ER+ Luminal A-like MCF7, ER+ Luminal B-like BT474 and ER- Basal-like BT549 breast cancer cell lines. Results: GOBO analysis revealed high levels of QSOX1 RNA expression in ER+ subtypes of breast cancer. In addition, Kaplan Meyer analyses revealed QSOX1 RNA as a highly significant predictive marker for both relapse and poor overall survival in Luminal B tumors. We confirmed this finding by evaluation of QSOX1 protein expression in breast tumors and in a panel of breast cancer cell lines. Expression of QSOX1 in breast tumors correlates with increasing tumor grade and high Ki-67 expression. Suppression of QSOX1 protein slowed cell proliferation as well as dramatic inhibition of MCF7, BT474 and BT549 breast tumor cells from invading through Matrigel™ in a modified Boyden chamber assay. Inhibition of invasion could be rescued by the exogenous addition of recombinant QSOX1. Gelatin zymography indicated that QSOX1 plays an important role in the function of MMP-9, a key mediator of breast cancer invasive behavior. Conclusions: Taken together, our results suggest that QSOX1 is a novel biomarker for risk of relapse and poor survival in Luminal B breast cancer, and has a pro-proliferative and pro-invasive role in malignant progression partly mediated through a decrease in MMP-9 functional activity.

Background: Leiomyosarcomas typically originate within smooth muscle cells. Leiomyosarcomas arising from the adrenal vein are rare malignancies associated with delayed diagnosis and poor prognosis. The most common vascular site of origin is the inferior vena cava. Case presentation: This is a 64-year old woman who presented with a 13 × 6.5 × 6.6 cm heterogeneous mass arising in the region of the right adrenal gland and extending into the inferior vena cava (IVC) and the right atrium. Biochemical evaluation excluded a functional tumor of the adrenal gland, and multiple tumor markers were negative. We present the novel use of deep hypothermic circulatory arrest (DHCA) in the resection of an adrenal vein leiomyosarcoma extending into the right atrium. The patient remains free of disease ten months after surgery. DHCA afforded a bloodless operative field for optimal resection of disease from within the IVC. Conclusion: The diagnosis of leiomyosarcomas of the adrenal vein is one of exclusion and involves preoperative radiological imaging and biochemical evaluation to exclude other functional tumors of the adrenal gland. Aggressive surgical resection is associated with improved survival and may be best achieved via collaboration among different surgical subspecialties.

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

Tumor-infiltrating lymphocytes (TILs) are prognostic in invasive breast cancer. However, their prognostic significance in ductal carcinoma in situ (DCIS) has been controversial. To investigate the prognostic role of TILs in DCIS outcome, we used different scoring methods for TILs in multi-national cohorts from Asian and European women. Self-described race was genetically confirmed using QC Infinium array combined with radmixture software. Stromal TILs, touching TILs, circumferential TILs, and hotspots were quantified on H&E-stained slides and correlated with the development of second breast cancer events (BCE) and other clinico-pathological variables. In univariate survival analysis, age older than 50 years, hormone receptor positivity and the presence of circumferential TILs were weakly associated with the absence of BCE at the 5-year follow-up in all cohorts (p < 0.03; p < 0.02; and p < 0.02, respectively, adjusted p = 0.11). In the multivariable analysis, circumferential TILs were an independent predictor of a better outcome (Wald test p = 0.01), whereas younger age was associated with BCE. Asian patients were younger with larger, higher grade, HR negative DCIS lesions, and higher TIL variables. The spatial arrangement of TILs may serve as a better prognostic indicator in DCIS cases than stromal TILs alone and may be added in guidelines for TILs evaluation in DCIS.

Medullary thyroid carcinoma (MTC) is a differentiated form of thyroid carcinoma that, in contrast to the more common follicular cell–derived carcinomas, arises from the calcitonin-secreting parafollicular C cells. The majority are sporadic, presenting as a solitary thyroid nodule in adulthood, whereas the less common hereditary forms present at an earlier age, typically as multifocal disease. In unsuspected patients, MTC is often at an advanced stage at the time of diagnosis. The diagnosis of MTC is almost always made by fine-needle aspiration (FNA) cytology in sporadic cases and often by serum calcitonin measurement in patients known to be at risk of hereditary disease. The variety of cytologic presentations of MTC introduces many possibilities in the differential diagnosis. The diagnostic accuracy of FNA can be enhanced by ancillary testing, specifically calcitonin and carcinoembryonic antigen immunohistochemistry or measurement of these tumor markers in serum or FNA washout fluid. Recognition of the role of mutations in the RET (REarranged during Transfection) proto-oncogene in the pathogenesis of MTC has led to the development of tests for screening, diagnosis, and prognostication. The mainstay of treatment is thyroidectomy with central neck lymph node dissection, which may be performed as a prophylactic procedure in patients with germline RET mutations. Given the suboptimal results of radiotherapy and chemotherapy, treatments that specifically target RET such as vandetanib and cabozantinib have shown promise in phase 3 clinical trials.