Fragile X mental retardation syndrome is caused by the unstable expansion of a CGG repeat in the FMR-1 gene. In patients with a full mutation, abnormal methylation results in suppression of FMR-1 transcription. FMR-1 is expressed in many tissues but its function is unknown. We have raised monoclonal antibodies specific for the FMR-1 protein. They detect 4-5 protein bands which appear identical in cells of normal males and of males carrying a premutation, but are absent in affected males with a full mutation. Immunohistochemistry shows a cytoplasmic localization of FMR-1. The highest levels were observed in neurons, while glial cells contain very low levels. In epithelial tissues, levels of FMR-1 were higher in dividing layers. In adult testis, FMR-1 was detected only in spermatogonia. FMR-1 was not detected in dermis and cardiac muscle except under pathological conditions.

ABSTRACT

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use.

The expression of the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied durin breast cancer progression. The ST3 gene Is expressed in all invadve breast cardnomas, in a number of their metes, and in some in situ cardnomas where the probability of deting ST3 transcripts correlates with the known risk of these carinomas to become invadve. ST3 Breast cancer, whose incidence is increasing worldwide, is a leading cause of cancer deaths among women in the industrialized world. While it is clear that more specific treatments are necessary, early detection based on mammography screening and a better administration of present systemic therapies should help to stabilize this unfavorable evolution (1). In this respect, there is a need for new prognostic and predictive factors to better define the patients who are the most likely to benefit from adjuvant therapy (1,2).In this context, we have designed a strategy based on the differential screening of breast cancer cDNA libraries to identify genes whose expression is modified in breast carcinomas and that may play a role in breast cancer progression. We have previously identified the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase (MMP) and represents a potential marker of tumor invasion (3,4). MMPs are believed to play a role in cancer progression (5, 6), and it has been proposed that they could cooperate with other types of secreted proteinases, including urokinase (7). In the present study, we demonstrate that ST3 gene expression is modulated during breast cancer progression, in ways suggesting that ST3 may be implicated from the earliest stages of tumor invasion. (Fig. 2 a-1). However, ST3 gene expression in in situ Abbreviations: ST1, ST2, and ST3, stromelysins 1, 2, and 3; IV COL(72), 72-kDa type IV coliagenase; MMP, matrix metalloproteinase. MATERIALS AND METHODS 1843The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.