Corneal Perforation with Preseptal Cellulitis in a Patient with Acute Lymphocytic Leukemia

We report a case of corneal perforation with preseptal cellulitis in a patient with acute lymphocytic leukemia (ALL). A 17-yr-old female patient who was undergoing combination chemotherapy for ALL was referred due to upper lid swelling and pain in the right eye for 2 days. Visual acuity in the right eye was 20/20. Initial examination showed no abnormal findings, other than swelling of the right upper eyelid. Computed tomography showed a finding of preseptal cellulitis. Microbiologic study of bloody and purulent discharge revealed Serratia marcescens. Corneal melting and perforation with iris prolapse were detected in the right eye on the 16th day. Emergent tectonic keratoplasty was performed. Seven months after surgery, visual acuity in the right eye was 20/300, and the corneal graft was stable

Fascin Is a Key Regulator of Breast Cancer Invasion That Acts via the Modification of Metastasis-Associated Molecules

The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting

FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T_regs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T_regsas a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated <it>in vitro </it>and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.</p> <p>Methods</p> <p>Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.</p> <p>Results</p> <p>A co-existence of B7-H1⁺T lymphocytes and FOXP3⁺T_regswas evidenced by the highly significant correlation of these molecules (<it>P </it>< .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3⁺T_regs, B7-H1⁺and PD-1⁺TIL synergistically correlated with high histological grade (III) (<it>P </it>< .001), estrogen receptor negative status (<it>P </it>= .017), and the presence of severe lymphocytic infiltration (<it>P </it>= .022).</p> <p>Conclusion</p> <p>Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T_regsand B7-H1/PD-1 molecules.</p

Translational Implications of Dysregulated Pathways and microRNA Regulation in Quadruple-Negative Breast Cancer

Triple-negative breast cancers (HER2&minus;, ER&minus;, PR&minus;) continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. microRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed

Translational Implications of Dysregulated Pathways and microRNA Regulation in Quadruple-Negative Breast Cancer

Triple-negative breast cancers (HER2−, ER−, PR−) continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. microRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed.</jats:p

Abstract P4-05-02: Role of the Atr Protein Kinase and Curcumin in Tumor-Stromal Interactions in Breast Cancer

Abstract Carcinoma-associated fibroblasts (CAFs) play important roles in the genesis and thrive of various types of epithelial cancers, including breast carcinomas. Indeed, various genetic and epigenetic variations have been identified in stromal fibroblasts, and we have recently shown that CAFs as well as their corresponding counterparts (TCFs) display neoplastic-specific changes (Hawsawi et al., 2008). We have also shown that the levels of the tumor suppressor proteins p53 and p21 are down-regulated in CAFs as compared to TCFs. During the cellular response to DNA damage these genes are under the control of important proteins such as Atr, a protein kinase essential for the maintenance of genomic integrity. To further elucidate the molecular changes that occur in breast cancer-associated fibroblasts we assessed the expression of Atr and have shown that the level of the Atr protein kinase is lower in 7 out of 10 (70%) CAFs as compared to their corresponding TCFs. Using specific ATR-siRNA we have shown that ATR negatively controls the expression of various proteins involved in the stromal-epithelial interactions. These include the stromal cell-derived factor 1 (SDF1), the vascular endothelial growth factor (VEGF) and the matrix metalloproteinase-2 (MMP2). In addition, the ELISA assay was used to show that the level of these proteins was higher in the conditioned media from stromal fibroblasts expressing specific ATR-siRNA as compared to control cells. Importantly, serum-free conditioned media from ATR-defective cells stimulated the proliferation and invasion/migration of cultured human breast cancer cells in an SDF1-dependent manner. These results clearly show the role of the breast stromal fibroblast Atr protein in suppressing tumoregenesis in the breast. Moreover, we have shown that curcumin can normalize the expression/secretion of these factors and therefore reduces the invasion/migration of breast cancer cells in vitro. This indicates that curcumin has potential use as stromal fibroblastnormalizing factor that can be utilized for the inhibition of both cancer initiation and recurrence. Hawsawi, N. M., Ghebeh, H., Hendrayani, S. F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S., and Aboussekhra, A. (2008). Cancer Res 68, 2717-2725. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-02.</jats:p