Epigenetic silencing of maspin gene expression in human breast cancers

Domann, Frederick E.; Rice, Judd C.; Hendrix, Mary J.C.; Futscher, Bernard W.

doi:10.1002/(sici)1097-0215(20000315)85:6<805::aid-ijc12>3.0.co;2-5

Cited by 164 publications

(137 citation statements)

References 17 publications

(21 reference statements)

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Maspin expression in normal skin and usual cutaneous carcinomas

et al. 2002

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Maspin is a serine protease inhibitor whose gene is located on 3q27. Several lines of evidence point towards its putative role as tumor suppressor gene and angiogenesis inhibitor; however, there are compelling data showing that maspin is also expressed in the nuclear compartment and might be associated with the differentiation of specific cell lineages. No systematic study of maspin expression in normal skin and usual skin carcinomas have been published so far. We semiquantitatively analyzed the distribution and immunoreactivity pattern of maspin in 14 squamous cell carcinomas (SCCs) and 16 basal cell carcinomas (BCCs) and in the adjacent normal epidermis of all cases. We also examined the correlation of maspin expression with histological type, grade, vascular invasion, perineural infiltration, and mitotic counting. Cytoplasmic expression of maspin was observed in suprabasal, prickle, and granular cell layers of normal epidermis; cells of the germinative hair matrix, Henle's and Huxley's layers, and cuticle of hair follicles; mature sebaceous cells and sweat gland's secretory cells. Nuclear expression was detected in some basal/myoepithelial cells of the sweat glands and scattered mature sebaceous cells. All SCCs but one grade IV SCC showed maspin expression, and it was correlated with the differentiation of these neoplasms. BCCs presented variable maspin expression, while metatypical carcinomas showed moderate to intense maspin expression, nodular BCCs variable contents of maspin and displayed a peculiar distribution, confined to the center of the neoplastic nodules. Two BCCs and one SCC showed maspin nuclear expression. No correlation with other clinical pathological features was observed. Our findings do not support the role of maspin as a tumor suppressor gene and suggest that this serpin is probably associated with specific lines of differentiation.

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Section: Discussionmentioning

confidence: 99%

Maspin expression in normal skin and usual cutaneous carcinomas

et al. 2002

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“…Domann et al [14] and Futscher et al [2] have shown that the silencing of maspin gene expression is inversely correlated with methylation of the promoter. Although the maspin gene is a potential clinical targeted invention, the regulating mechanism remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…Although the maspin gene is a potential clinical targeted invention, the regulating mechanism remains to be elucidated. Domann et al [14] have shown that 5-Aza-2'-deoxycytidine (5-Aza-dC), known to be a demethylating agent, causes maspin mRNA levels to recover and suggests that methylation at CpGs, located in the maspin promoter, is the only impediment to maspin expression in a nonexpressing tissue. The maspin proximal promoter harbors many CpGs.…”

Section: Introductionmentioning

confidence: 99%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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Summary Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-Aza-2'-deoxycytidine (5-Aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5Aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5Aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5Aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 hours after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a histone deacetylase inhibitor, in cancer therapy.

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“…This offers a unique opportunity for therapeutic intervention through specific re-activation of the endogenous gene. Maspin silencing involves: (1) transcriptional regulation (by means of TFs such as p53 (Zhou et al, 2000), ETS, AP-1 (Zhang et al, 1997), hormone receptor (Zhang et al, 1997;Khalkhali-Ellis et al, 2004) and aberrant promoter methylation (Domann et al, 2000;Futscher et al, 2002). (2) High levels of maspin are associated not only with reduction of tumor growth , but also decreased angiogenesis (Zhang et al, 2000a), cell motility and invasion (Sheng et al, 1996;Seftor et al, 1998), and metastatic dissemination (Zhang et al, 2000b;Shi et al, 2002;Cher et al, 2003;Watanabe et al, 2005).…”

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confidence: 99%

Re-activation of a dormant tumor suppressor gene maspin by designed transcription factors

et al. 2006

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The controlled and specific re-activation of endogenous tumor suppressors in cancer cells represents an important therapeutic strategy to block tumor growth and subsequent progression. Other than ectopic delivery of tumor suppressor-encoded cDNA, there are no therapeutic tools able to specifically re-activate tumor suppressor genes that are silenced in tumor cells. Herein, we describe a novel approach to specifically regulate dormant tumor suppressors in aggressive cancer cells. We have targeted the Mammary Serine Protease Inhibitor (maspin) (SERPINB5) tumor suppressor, which is silenced by transcriptional and aberrant promoter methylation in aggressive epithelial tumors. Maspin is a multifaceted protein, regulating tumor cell homeostasis through inhibition of cell growth, motility and invasion. We have constructed artificial transcription factors (ATFs) made of six zinc-finger (ZF) domains targeted against 18-base pair (bp) unique sequences in the maspin promoter. The ZFs were linked to the activator domain VP64 and delivered in breast tumor cells. We found that the designed ATFs specifically interact with their cognate targets in vitro with high affinity and selectivity. One ATF was able to re-activate maspin in cell lines that comprise a maspin promoter silenced by epigenetic mechanisms. Consistently, we found that this ATF was a powerful inducer of apoptosis and was able to knock down tumor cell invasion in vitro. Moreover, this ATF was able to suppress MDA-MB-231 growth in a xenograft breast cancer model in nude mice. Our work suggests that ATFs could be used in cancer therapeutics as novel molecular switches to re-activate dormant tumor suppressors.

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Epigenetic silencing of maspin gene expression in human breast cancers

Cited by 164 publications

References 17 publications

Maspin expression in normal skin and usual cutaneous carcinomas

Maspin expression in normal skin and usual cutaneous carcinomas

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Re-activation of a dormant tumor suppressor gene maspin by designed transcription factors

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