p53 and breast cancer

Ziyaie, Dorin; Hupp, Ted R.; Thompson, Alastair

doi:10.1054/brst.2000.0199

Cited by 32 publications

(17 citation statements)

References 84 publications

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“…These tumors are estrogen-independent and lack functional p53 and Rb mutations, alterations of which have been detected in human breast cancers (17,18). The growth inhibitory effects of MIS could be beneficial in the treatment͞prevention of these hormone refractory mammary tumors, especially because high levels of MIS have not shown any harmful effects in humans (30), and the serum levels used here are well below those sustained in normal healthy postnatal to prepubertal boys (26).…”

Section: Discussionmentioning

confidence: 81%

“…Mutations in Rb are prevalent in 20% of human breast cancers and p53 mutations͞alterations are detected in Ϸ50% of primary human breast tumors (17,18), suggesting that inactivation of these two tumor suppressors may be critical in human breast tumorigenesis. The estrogen receptor-negative human breast cancer cell line MDA-MB-468 is Rb negative, harbors mutant p53, overexpresses the EGF receptor (19), and is highly responsive to MIS treatment in vitro (20).…”

Section: Mullerian Inhibiting Substance (Mis) Inhibits Breast Cancer mentioning

confidence: 99%

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Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Gupta

Carey

Kawakubo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro.To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P ‫؍‬ 0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P ‫؍‬ 0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor-and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P ‫؍‬ 0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.proliferation ͉ apoptosis ͉ simian virus 40 large T antigen M ullerian inhibiting substance (MIS) is a member of the TGF-␤ family, a class of molecules that govern a myriad of cellular processes including growth, differentiation, and apoptosis. Synthesis of MIS demonstrates a sexually dimorphic pattern and is produced by Sertoli cells of the fetal and adult testis and granulosa cells of the postnatal ovary. In male embryos, MIS causes regression of the Mullerian duct, the anlagen of the Fallopian tubes, uterus, and upper vagina (1). However, a postnatal role for MIS in males and females has yet to be defined. Signaling by MIS is propagated by binding of MIS to the MIS type II receptor, a transmembrane serine, threonine kinase expressed at high levels in the Mullerian duct, Sertoli cells, and granulosa cells of the embryonic and adult gonads and in the uterus (2-4). The MIS-bound type II receptor subsequently recruits a type I receptor. Activin-like kinase 2 (ALK2), ALK3, and ALK6 have been implicated in mediating MIS signaling in cells (5-9).We recently demonstrated the presence of MIS receptors in mammary tissue and breast cancer cell lines, suggesting that the mammary gland is a likely target for MIS (6,10,11). In the rat mammary gland, expression of the MIS type II receptor is suppressed during puberty when the ductal system branches and invades the adipose stroma and during massive expansion at pregnancy and lactation, but is up-regulated during involution, a ti...

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Section: Discussionmentioning

confidence: 81%

Section: Mullerian Inhibiting Substance (Mis) Inhibits Breast Cancer mentioning

confidence: 99%

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Gupta

Carey

Kawakubo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…p53 is a key gene involved in tumour response to therapy, integrating cellular stress including the action of chemotherapy agents resulting in a range of responses including cell cycle arrest and apoptosis Vogelstein et al, 2000;Ziyaie et al, 2000).…”

mentioning

confidence: 99%

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

et al. 2003

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In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.

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“…At least two regions on 17p have been identified in loss of heterozygosity (LOH) or allelic imbalance studies of paired blood and breast cancer DNA (Stack et al, 1995). One of these regions, the p53 gene at 17p13.1, has attracted wide attention as a tumour suppressor gene, transcription factor and mediator of apoptosis in many types of cancer (Steele et al, 1999), including breast cancer (Ziyaie et al, 2000). A second region, defined by markers YNZ22 (D17S5) and 144D6 (D17S30), is situated in band 17p13.3, 20 Mb telomeric to the p53 tumour suppressor gene, and may contain more than one gene involved in carcinogenesis.…”

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confidence: 99%

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

et al. 2001

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Summary A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2′-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

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p53 and breast cancer

Cited by 32 publications

References 84 publications

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

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