Purpose: Classic lobular carcinomas (CLC) account for 10% to 15% of all breast cancers. At the genetic level, CLCs show recurrent physical loss of chromosome16q coupled with the lack of E-cadherin (CDH1 gene) expression. However, little is known about the putative therapeutic targets for these tumors. The aim of this study was to characterize CLCs at the molecular genetic level and identify putative therapeutic targets. Experimental Design: We subjected 13 cases of CLC to a comprehensive molecular analysis including immunohistochemistry for E-cadherin, estrogen and progesterone receptors, HER2/ neu and p53; high-resolution comparative genomic hybridization (HR-CGH); microarray-based CGH (aCGH); and fluorescent and chromogenic in situ hybridization for CCND1 and FGFR1. Results: All cases lacked the expression of E-cadherin, p53, and HER2, and all but one case was positive for estrogen receptors. HR-CGH revealed recurrent gains on 1q and losses on 16q (both, 85%). aCGH showed a good agreement with but higher resolution and sensitivity than HR-CGH. Recurrent, high level gains at 11q13 (CCND1) and 8p12-p11.2 were identified in seven and six cases, respectively, and were validated with in situ hybridization. Examination of aCGH and the gene expression profile data of the cell lines, MDA-MB-134 and ZR-75-1, which harbor distinct gains of 8p12-p11.2, identified FGFR1 as a putative amplicon driver of 8p12-p11.2 amplification in MDA-MB-134. Inhibition of FGFR1 expression using small interfering RNA or a small-molecule chemical inhibitor showed that FGFR1 signaling contributes to the survival of MDA-MB-134 cells. Conclusions: Our findings suggest that receptor FGFR1 inhibitors may be useful as therapeutics in a subset of CLCs.

These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.

The use of cancer biomarkers to anticipate the outlines of disease has been an emerging issue, especially as cancer treatment has made such positive steps in the last few years. Progress in the development of consistent malignancy markers is imminent because advances in genomics and bioinformatics have allowed the examination of immense amounts of data. Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, and activated T lymphocytes, and is present in extracellular fluids, at sites of inflammation, and in the extracellular matrix of mineralized tissues. Several physiologic roles have been attributed to osteopontin, i.e., in inflammation and immune function, in mineralized tissues, in vascular tissue, and in kidney. Osteopontin interacts with a variety of cell surface receptors, including several integrins and CD44. Binding of osteopontin to these cell surface receptors stimulates cell adhesion, migration, and specific signaling functions. Overexpression of osteopontin has been found in a variety of cancers, including breast cancer, lung cancer, colorectal cancer, stomach cancer, ovarian cancer, and melanoma. Moreover, osteopontin is present in elevated levels in the blood and plasma of some patients with metastatic cancers. Therefore, suppression of the action of osteopontin may confer significant therapeutic activity, and several strategies for bringing about this suppression have been identified. This review looks at the recent advances in understanding the possible mechanisms by which osteopontin may contribute functionally to malignancy, particularly in breast cancer. Furthermore, the measurement of osteopontin in the blood or tumors of patients with cancer, as a way of providing valuable prognostic information, will be discussed based on emerging clinical data. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1087 -97)

p63 is a recently characterized p53-homolog that is consistently expressed by basal/somatic stem cells of stratified epithelia, myoepithelial cells of the breast and salivary glands, and proliferative compartment of gastric mucosa. p63 is located on the long arm of chromosome 3 (3q27) and it encodes six isoforms, three transactivating (TA) and three DeltaN-isoforms. While the first three isoforms may act as tumor suppressor genes, the DeltaN-isoforms may inhibit the p53/TA-p63-driven cell cycle arrest and apoptosis. Recently, the putative applications of p63 in the identification of myoepithelial cells of the breast and basal cells of the prostate acini have been evaluated; however, no critical systematic analysis of its role in surgical pathology practice have hitherto been reported. We review the putative roles of p63 in surgical pathology practice and provide guidelines for future directions on p63 translational research.

The clinical significance of ERBB2 amplification/overexpression in gastric cancer remains unclear. In this study, we evaluated the ERBB2 status in 463 gastric carcinomas using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), and compared the findings with histopathological characteristics and with disease-specific survival. ERBB2 overexpression (2 þ and 3 þ ) and amplification (ratio ERBB2/CEP17X2) were found in 43 (9.3%) and 38 (8.2%) gastric carcinomas, respectively. Perfect IHC/FISH correlation was found for the 19 cases scored as 0 (all negative by FISH), and also for the 25 cases scored as 3 þ (all positive by FISH). One out of six carcinomas scored as 1 þ and 12 out of 18 carcinomas scored as 2 þ were positive by FISH. ERBB2 amplification was associated with gastric carcinomas of intestinal type (P ¼ 0.007) and with an expansive growth pattern (P ¼ 0.021). ERBB2 amplification was detected in both histological components of two mixed carcinomas, indicating a common clonal origin. A statistically significant association was found between ERBB2 amplification and worse survival in patients with expansive gastric carcinomas (P ¼ 0.011). We conclude that ERBB2 status may have clinical significance in subsets of gastric cancer patients, and that further studies are warranted to evaluate whether patients whose gastric carcinomas present ERBB2 amplification/overexpression may benefit from therapy targeting this surface receptor. Despite the trend for decreasing incidence, gastric adenocarcinoma is still the second cause of cancer death worldwide (Parkin et al, 2005). The overall 5-year survival rate of patients with resectable gastric cancer ranges from 10 to 30% (Harrison et al, 1998;Msika et al, 2000;Green et al, 2002). Apart from surgical resection, evaluation of available therapies, both neo-adjuvant and adjuvant, provides conflicting results regarding the clinical outcome. Several meta-analyses have been published in an attempt to address the discrepancies reported in the literature, but recommendation for adjuvant chemotherapy in Western centres is still not consensual (Hermans et al, 1993;Earle and Maroun, 1999;Mari et al, 2000;Gianni et al, 2001;Janunger et al, 2001Janunger et al, , 2002Hu et al, 2002). The most important prognostic factor established for gastric cancer is the TNM stage, which is determined by the depth of invasion, involvement of lymph nodes, and distant metastasis. However, clinical outcome varies among patients in the same stage (Park et al, 2006). Therefore prognostic factors other than the TNM stage, as well as new therapies, would be of great value for gastric cancer patients.The ERBB2 gene maps to 17q12 -q21 and encodes a 185-kDa transmembrane tyrosine kinase receptor (p185), which is a member of the epidermal growth factor receptor family (Xu et al, 1984;Akiyama et al, 1986;Popescu et al, 1989). In breast carcinomas, ERBB2 functions as an oncogene, as amplification of the gene induces protein overexpression in the cell membrane (Slamon et al, 1989). Besides ...