Maspin expression inversely correlates with breast tumor progression in MMTV/TGF-alpha transgenic mouse model

Abstract

Maspin is a novel serine protease inhibitor (serpin) with tumor suppressive activity. To date, despite the mounting evidence implicating the potential diagnostic/prognostic and therapeutic value of maspin in breast and prostate carcinoma, the lack of a suitable animal model hampers the in vivo investigation on the role of maspin at dierent stages of tumor progression. In this study, we used MMTV/TGF-a transgenic mouse model to study the expression pro®le of maspin in mammary tumor progression.Histopathological examinations of MMTV/TGF-a transgenic mice revealed TGF-a expression leading to hyperproliferation, hyperplasia, and occasional carcinoma in mammary gland. Interestingly, when MMTV/TGF-a transgenic mice were breed to homozygocity, they also developed characteristic skin papillomas. Immunohistochemistry analysis of maspin expression in the breast tissues of TGF-a transgenic mice showed a direct correlation between down-regulation of maspin expression and tumor progression. The loss of maspin expression was concomitant with the critical transition from carcinoma in situ to invasive carcinoma. Subsequent in-situ hybridization analyses suggest that the down-regulation of maspin expression is primarily a transcriptional event. This data is consistent with the tumor suppressive role of maspin. Furthermore, our data suggests that MMTV/TGF-a transgenic mouse model is advantageous for in vivo evaluation of both the expression and the biological function of maspin during the slow multi-stage carcinogenesis of mammary gland. Oncogene (2001) 20, 6538 ± 6543.

Maspin expression in normal skin and usual cutaneous carcinomas

“…Maspin is one of the serpins that have received great attention by basic researchers and pathologists during the past few years [9,5,6,11,12,14,15,16,17,18,20,21,22,23,24,25,27,28,31,35,36,37]. Since its characterization several biological properties have been attributed to maspin, including tumor suppressor and antiangiogenic activities [9,14,15,22,27,28,36,37].…”

“…Since its characterization several biological properties have been attributed to maspin, including tumor suppressor and antiangiogenic activities [9,14,15,22,27,28,36,37]. It is also considered as a suppressor of invasion, motility, proliferation, and metastatic potential of neoplastic cells [9,5,6,11,12,14,15,16,17,18,20,21,22,23,24,25,27,28,31,35,36,37].…”

“…Its gene is located on 18q21 and encodes a serine protease inhibitor of 42 kDa that putatively has tumor suppressor [9,14,15,22,27,28,37] and antiangiogenic activity [9,14,36,37]. Moreover it has been proposed that maspin blocks plasminogen activator [27,28], a factor that mediates cellular invasion and migration.…”

“…Moreover it has been proposed that maspin blocks plasminogen activator [27,28], a factor that mediates cellular invasion and migration. Despite the huge amount of data concerning the expression of maspin and its correlations with biological properties of human breast [9,14,15,22,27,28,36,37], prostate [18,27,31,35], and pancreatic carcinomas [16,17] and cell lines [9,14,15,16,17,18,22,27,28,31,35,36,37], little is know on maspin expression in other tissues.…”

Convergence of p53 and Transforming Growth Factor β (TGFβ) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells

“…Maspin protein is expressed in non-tumor mammary epithelial cells but is absent in most breast cancer cell lines (14). In MMTV/TGF␣ transgenic mice, Maspin expression inversely correlates with mammary tumor progression (27). Restoration of Maspin protein expression in MDA-MB-435 breast cancer cells reduces the abilities of these cells to form tumors and metastasize in nude mice (14).…”