Down‐regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion

Abstract

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin-fixed paraffin-embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows -- normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that down-regulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations -- tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between down-regulated gelsolin expression in the DCIS component and size (< versus > or = 15 mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P < 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.

Regulation of Intercellular Adhesion Strength in Fibroblasts

“…The reduction in cadherin-mediated adhesion strength, which compromises the integrity of intercellular contacts prior to metastasis, may result from reduced gelsolin expression or function. Indeed, down-regulation of gelsolin expression coincides with tumor invasiveness and has been implicated as a prognostic indicator for therapeutic interventions in cancer (59). We found that gelsolin-null cells demonstrated a defect in the maturation of cadherin-mediated adhesions, which resulted in reductions in the strength of intercellular contacts.…”

Tumor-Associated Macrophages Promote Epigenetic Silencing of Gelsolin through DNA Methyltransferase 1 in Gastric Cancer Cells

“…GSN, downregulated in various cancers such as ovarian cancer, skin cancer, breast cancer, and bladder cancer, is a tumor suppressor (11,(13)(14)(15). In breast and ovarian cancer, loss of GSN is likely caused by an epigenetic-related mechanism (15, 16); however, ubiquitin-mediated degradation may decrease GSN expression in pancreatic cancer (38), suggesting that GSN dysregulation is a convergent consequence from different mechanisms in various cancers.…”

“…Gelsolin (GSN) is an actin-binding protein that controls actin filament assembly and disassembly by severing, capping, and nucleating F-actin (9). GSN expression is downregulated in many cancers (10)(11)(12)(13) and GSN overexpression leads to reduced cell growth, tumorigenicity, and metastasis in cell lines of human bladder cancer and mouse melanoma (11,14), suggesting its potential role in tumor suppression. Because no major mutation, rearrangement, and deletions have been identified in the GSN gene, inactivation of GSN in tumors may occur through epigenetic mechanisms, such as DNA methylation and histone modifications (15,16).…”

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

“…In vivo studies using MMTV-Her2/neu transgenic mice have shown downregulation of gelsolin at the mRNA level in primary mammary tumors in comparison to the normal mammary gland (31). Furthermore, it was showed that gelsolin expression was reduced in human mammary lesions as the disease progressed; atypical ductal hyperplasia!ductal carcinoma in situ!invasive carcinoma (32)(33)(34). However, a previous report indicated that gelsolin levels were increased in the plasma of breast cancer patients (35), suggesting the role of gelsolin in carcinogenesis needs to be further investigated.…”