<i>p53</i> Loss Synergizes with Estrogen and Papillomaviral Oncogenes to Induce Cervical and Breast Cancers

Shai, Anny; Pitot, Henry C.; Lambert, Paul F.

doi:10.1158/0008-5472.can-07-5266

Cited by 52 publications

(52 citation statements)

References 44 publications

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“…K14Crep53 F/F mice were shown previously to develop tumors with ERα-negative cells in the absence of exogenous estrogen and often ERα-positive tumors after treatment with estrogen [16, 17]. ERα-positive tumors also developed under the conditional inactivation of p53 by the WAP Cre linking the expression of ERα in mammary tumors to the time of p53 inactivation during mammary gland development [26].…”

Section: Resultsmentioning

confidence: 99%

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

et al. 2017

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BackgroundUpregulation of estrogen receptor beta (ERβ) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERβ and breast carcinogenesis is still missing.MethodsTo study the role of ERβ in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERβ and p53 in the mammary gland epithelium. For epithelium-specific knockout of ERβ and p53, ERβ F/F and p53 F/F mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter.ResultsSomatic loss of ERβ significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers.ConclusionsOur results show that synergism between ERβ and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0872-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

et al. 2017

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“…During adolescence and pregnancy, the cervix is exposed to augmented levels of hormonal changes (Singer and Monaghan, 2000), in which oestrogen stimulation facilitates acidification of the vaginal cavity, a determinant of squamous metaplasia when the endocervical epithelial everts (Elson et al, 2000). When this oestrogen-stimulated metaplastic transformation occurs in the presence of HPV, the probability of cell transformation increases, resulting in neoplastic changes (Elson et al, 2000;Shai et al, 2007Shai et al, , 2008Hwang et al, 2009). This phenomenon is dependent primarily on parity, and is more likely to occur during the first pregnancy rather than subsequent pregnancies (Singer and Monaghan, 2000).…”

Section: Discussionmentioning

confidence: 99%

Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries

et al. 2009

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Early age at first sexual intercourse (AFSI) has long been associated with an increased risk of invasive cervical carcinoma (ICC). Age at first pregnancy (AFP) and ICC have been investigated less, although AFSI and AFP are strongly interrelated in most developing countries. A pooled analysis of case -control studies on ICC from eight developing countries with 1864 cases and 1719 controls investigated the roles of AFSI, AFP, and ICC risk. Age at first sexual intercourse, AFP and age at first marriage (AFM) were highly interrelated and had similar ICC risk estimates. Compared with women with AFSI X21 years, the odds ratio (OR) of ICC was 1.80 (95% CI: 1.50 -2.39) among women with AFSI 17 -20 years and 2.31 (95% CI: 1.85 -2.87) for AFSI p16 years (P-trend o0.001).No statistical interaction was detected between AFSI and any established risk factors for ICC. The ICC risk was 2.4-fold among those who reported AFSI and AFP at p16 years compared with those with AFSI and AFP at X21 years. These data confirm AFSI and AFB as risk factors for ICC in eight developing countries, but any independent effects of these two events could not be distinguished.

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“…In the reproductive tract, E6 has significantly weaker activity than E7 (Riley et al, 2003); however, after prolonged oestrogen treatment, cervical tumours did result, although this activity did not seem to require PDZ-binding capacity (Shai et al, 2007). Most importantly, however, the ability of E6 to cooperate with E7 in increasing tumour size and frequency, both in the cervix and at other tumour sites, was dependent upon the ability of E6 to bind to its PDZ domain-containing substrates (Nguyen et al, 2003;Shai et al, 2007Shai et al, , 2008. Obviously, the prime candidates for these activities of E6 are those substrates implicated in the regulation of cell polarity (see below), but the dissection of which target(s) is involved will require further dissection of E6's PDZ-binding capacity, as well as the use of conditional knockout mice in some of the polarity candidates.…”

Section: Biological Consequences Of Hpv E6 Interaction With Pdz-contamentioning

confidence: 99%

Human papillomaviruses, cervical cancer and cell polarity

et al. 2008

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Human papillomaviruses (HPVs) are the causative agents of a number of human cancers, of which cervical cancer is the most important. This occurs following persistent infection with a limited number of viral subtypes and is characterized by continued expression of the viral E6 and E7 oncoproteins. A unique characteristic of the cancercausing HPV types is the presence of a PDZ recognition motif on the carboxy terminus of the E6 oncoprotein. Through this motif, E6 directs the proteasome-mediated degradation of cellular proteins involved in the regulation of cell polarity and in cell proliferation control. These include components of the Scrib and Par polarity complexes, as well as a number of other PDZ domaincontaining substrates. Thus, PVs are now providing novel insights into the functioning of many of these cellular proteins, and into which of these functions, in particular, are relevant for maintaining normal cellular homeostasis. In this review, we discuss the biological consequences of papillomaviral targeting of these cell polarity regulators, both with respect to the viral life cycle and, most importantly, to the development of HPV-induced malignancy.

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p53 Loss Synergizes with Estrogen and Papillomaviral Oncogenes to Induce Cervical and Breast Cancers

Abstract: Whereas the tumor suppressor p53 gene is frequently mutated in most human cancers, this is not the case in human papillomavirus (HPV)-associated cancers, presumably because the viral E6 oncoprotein inactivates the p53 protein.

Cited by 52 publications

References 44 publications

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries

Human papillomaviruses, cervical cancer and cell polarity

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