Regulation of tumor suppressor proteins, p53 and retinoblastoma, by estrogen and antiestrogens in breast cancer cells

Hurd, Cliff; Khattree, Nidhi; Dinda, Sumi; Alban, Paul; Moudgil, Virinder K.

doi:10.1038/sj.onc.1201233

Cited by 67 publications

(50 citation statements)

References 22 publications

(28 reference statements)

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“…32 It is not known why increased exposure to estrogen may lower HCC risk, but experimental data suggest that estrogen can induce expression of certain tumor suppressor genes. 40,41 Otherwise, estradiol is catabolized mainly by hydroxylation reaction. Its 2-hydroxy metabolite can be converted to 2-methoxyestradiol by catechol O-methyltransferase, an enzyme with high levels in the liver.…”

Section: Discussionmentioning

confidence: 99%

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk

Chang

et al. 2003

Hepatology

106

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Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and firstdegree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P trend ‫؍‬ .0216) and age at natural menopause (P trend ‫؍‬ .0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age <50 during premenopausal years was also a risk factor (multivariate-adjusted OR, 2.57; 95% CI, H epatocellular carcinoma (HCC) is a highly malignant disease characterized by a striking male predominance; the male-to-female ratios in the incidence of HCC range from 2 to 4 in geographically diverse populations. 1,2 This gender difference may be, at least in part, attributable to differences in exposure to lifestyle risk factors for HCC, such as alcohol consumption and cigarette smoking. 3,4 However, sex hormone and X-linked genetic factors may also be important.Estrogen receptors exist in both mammalian and human livers. [5][6][7][8] In experimental rats and mice, there is also a greater preponderance of HCC in male subjects compared with female subjects. This sex difference has been observed in various animal models, including transgenic mice expressing hepatitis B or C viral proteins. [9][10][11][12][13][14][15] In addition, ovariectomy in mice increased susceptibility to chemically induced hepatocarcinogenesis. 11,16 Although these observations may suggest some role for endogenous estrogen in the etiology of HCC in humans, these aspects received relatively scant attention. [17][18][19] Exogenous estrogen use may also be associated with the risk of HCC. Several case reports have described the occurrence of liver adenomas or focal nodular hyperplasia in women taking oral contraceptives, 20 and the possible association between use of oral contraceptives and the risk of HCC has been assessed in several studies. 3,17,[21][22][23][24][25][26][27] However, most of these studies were based on a very limited number of case subjects, and the results have been incon-

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Section: Discussionmentioning

confidence: 99%

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk

Chang

et al. 2003

Hepatology

106

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“…This condition has been shown to reduce basal levels of p53 in estrogen-dependent breast cancer cell lines (Hurd et al, 1997). At protein level, estrogen deprivation resulted in a marked decrease in p53 and Hdm2 expression after long deprivation times.…”

Section: D133p53 Expression Correlates With P53 Protein Levelsmentioning

confidence: 99%

p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter

et al. 2010

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The tumor suppressor p53 protein is activated by genotoxic stress and regulates genes involved in senescence, apoptosis and cell-cycle arrest. Nine p53 isoforms have been described that may modulate suppressive functions of the canonical p53 protein. Among them, D133p53 lacks the 132 proximal residues and has been shown to modulate p53-induced apoptosis and cell-cycle arrest. D133p53 is expressed from a specific mRNA, p53I4, driven by an alternative promoter P2 located between intron 1 and exon 5 of TP53 gene. Here, we report that the P2 promoter is regulated in a p53-dependent manner. D133p53 expression is increased in response to DNA damage by doxorubicin in p53 wild-type cell lines, but not in p53-mutated cells. Chromatin immunoprecipitation and luciferase assays using P2 promoter deletion constructs indicate that p53 binds functional response elements located within the P2 promoter. We also show that D133p53 does not bind specifically to p53 consensus DNA sequence in vitro, but competes with wild-type p53 in specific DNA-binding assays. Finally, we report that D133p53 counteracts p53-dependent growth suppression in clonogenic assays. These observations indicate that D133p53 is a novel target of p53 that may participate in a negative feedback loop controlling p53 function.

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“…The induction of p53 by E 2 occurs prior to hyperphosphorylation of pRB and can be blocked by antiestrogens (Hurd et al, 1995(Hurd et al, , 1997. This suggested that ER acts as a master switch, regulating both a proliferative pathway (cyclin D1 expression-pRB) and in parallel an anti-proliferative pathway involving induction of p53.…”

Section: Introductionmentioning

confidence: 98%

“…Each appears to play a crucial role in apoptosis or programmed cell death, a process thought to be crucial for destroying tumor cells (Evan et al, 1992;Hermeking and Eick, 1994;Lowe et al, 1993Lowe et al, , 1994Hass-Kogan et al, 1995). The proliferative steroid hormone, E 2 has been implicated as an upstream regulator of all three proteins (Hurd et al, 1995(Hurd et al, , 1997Dubick and Shiu, 1988;Altucci et al, 1996;Lukas et al, 1996;Foster and Wimalasena, 1996;Planas-Silva andWeinberg, 1997, Prall et al, 1997), suggesting that E 2 might coordinate their expression in estrogen target tissues.…”

Section: Introductionmentioning

confidence: 99%

Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells

et al. 1999

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Loss of p53 function by mutational inactivation is the most common marker of the cancerous phenotype. Previous studies from our laboratory have demonstrated 17 b estradiol (E 2 ) induction of p53 protein expression in breast cancer cells. Although direct eects of E 2 on the expression of p53 gene are not known, the steroid is a potent regulator of c-Myc transcription. In the present studies, we have examined the ability of E 2 and antiestrogens to regulate the P1 promoter of the p53 gene which contains a c-Myc responsive element. Estrogen receptor (ER)-positive T47D and MCF-7 cells were transiently transfected with the P1CAT reporter plasmid and levels of CAT activity in response to serum, E 2 and antiestrogens were monitored. Factors in serum were noted to be the dominant inducers of chloramphenicol acetyltransferase (CAT) expression in MCF-7 cells. The levels of CAT were drastically reduced when cells were maintained in serum free medium (SFM). However, a subtle ER-mediated induction of CAT expression was detectable when MCF-7 cells, cultured in SFM, were treated with E 2 . In serum-stimulated T47D cells, the CAT expression was minimal. The full ER antagonist, ICI 182 780 (ICI) had no eect. Treatment with E 2 or 4-hydroxy tamoxifen (OHT) resulted in P1CAT induction; OHT was more eective than E 2 . Consistent with c-Myc regulation of the P1 promoter, E 2 stimulated endogenous c-Myc in both cell lines. Two forms of c-Myc were expressed independent of E 2 stimuli. The expression of a third more rapidly migrating form was E 2 -dependent and ER-mediated since it was blocked by the full ER antagonist, ICI, but not by the ER agonist/antagonist OHT. These data demonstrate both ER-mediated and ER-independent regulation of c-Myc and the P1 promoter of the p53 gene, and show dierential eects of the two classes of antiestrogens in their ability to induce the P1 promoter of the p53 gene in breast cancer cells.

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Regulation of tumor suppressor proteins, p53 and retinoblastoma, by estrogen and antiestrogens in breast cancer cells

Cited by 67 publications

References 22 publications

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk

p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter

Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells

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