Role of cell‐cycle regulatory proteins in gynecological cancer

Milde‐Langosch, Karin

doi:10.1002/jcp.10286

Cited by 48 publications

(46 citation statements)

References 214 publications

(350 reference statements)

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“…Milde-Langosch et al (15,16) detected cyclin D2 protein expression in all analyzed granulosa cell tumors (n ϭ 7) but in only 23% of 93 ovarian epithelial carcinomas. Thus, cyclin D2 overexpression is characteristic of a single histologic tumor type that accounts for 6% of all ovarian malignancies.…”

Section: G 1 Regulatorsmentioning

confidence: 95%

Cell Cycle Genes in Ovarian Cancer

D’Andrilli

Kumar

Scambia

et al. 2004

Clinical Cancer Research

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Human malignant tumors are characterized by abnormal proliferation resulting from alterations in cell cycleregulatory mechanisms. The regulatory pathways controlling cell cycle phases include several oncogenes and tumor suppressor genes that display a range of abnormalities with potential usefulness as markers of evolution or treatment response in ovarian cancer. This review summarizes the current knowledge about these aberrations in malignant tumors of the ovary. We sought to divide cell cycle-regulatory genes into four subgroups on the basis of their predominant role in a specific phase or during the transition between two phases of the cell cycle.

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Section: G 1 Regulatorsmentioning

confidence: 95%

Cell Cycle Genes in Ovarian Cancer

D’Andrilli

Kumar

Scambia

et al. 2004

Clinical Cancer Research

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“…Other cancers, including high-grade serous ovarian carcinoma, a subset of lung cancers, and highly aggressive breast and prostate cancers, also express high levels of p16 INK4A (24,(37)(38)(39)(40)(41). Such high-level p16 INK4A -expressing cancers generally also have pRB mutations (reviewed in ref.…”

Section: Cervical Cancer Cells Are Sensitive To Treatment With the Kdmentioning

confidence: 99%

Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

McLaughlin-Drubin

Park²,

Münger

2013

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

155

153

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The tumor suppressor p16 INK4A inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins. Oncogenic stress induces p16 INK4A expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor. Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16 INK4A activity by mutation or epigenetic silencing. Human papillomavirus (HPV)-associated tumors express high levels of p16 INK4A in response to E7 oncoprotein expression. Induction of p16 INK4A expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B. HPV E7 expression causes an acute dependence on KDM6B expression for cell survival. The p16 INK4A tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival. This oncogenic p16 INK4A activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive. Finally, we note that HPV E7 expression creates a unique cellular vulnerability to small-molecule KDM6A/B inhibitors.synthetic lethality | apoptosis | biomarker | cancer therapy P osttranslational histone modifications, including phosphorylation, ubiquitination, acetylation, and methylation, impact both the physical state and the transcriptional competence of chromatin. These modifications are dynamic and regulate a variety of cellular processes, such as stem cell maintenance, cell fate determination and maintenance, cell cycle control, and epigenetic heritability of transcriptional programs (reviewed in refs. 1 and 2). Methylation of lysine residues on histones is modulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). Although histone lysine methylation is involved in both transcriptional activation and repression, histone H3 trimethylation of lysine 27 (H3K27me3) on gene promoters is crucial for epigenetic silencing mediated by polycomb group proteins (3-5). The JmjC-domain containing histone demethylases, KDM6A (UTX) and KDM6B (JMJD3) remove this repressive mark, allowing for transcriptional activation (6-10). Although KDM6A and KDM6B appear identical with regards to catalytic activities and histone substrate specificities, they have a number of nonoverlapping and nonredundant biological activities. KDM6B-but not KDM6A-regulates RAS/RAF-mediated oncogene-induced senescence (OIS) (11, 12). OIS was originally described as a cell-abortive response to ectopic RAS oncogene expression in normal human cells. It is now recognized that OIS represents one of several cell-intrinsic tumor-suppressor responses that function to eliminate aberrantly proliferating, potentially premalignant cells. Evidence for OIS has been dete...

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“…[6][7][8] Studies of expression of these markers in cervical cancers have produced inconsistent results. 6,9,10,22 Less is known of the relationships between HPV status and p21 and p27 expression in tonsillar cancer, but no associations were identified in our recent series. 15 Since there have been few, if any, studies of the expression of these cell cycle proteins in HPVpositive cancers at different mucosal sites from patients with different ethnic backgrounds where the same experimental conditions have been used throughout, the observed discrepancies may reflect biological issues such as ethnicity or HPV type, or technical factors such as the specificities of the various antibodies or experimental protocols.…”

mentioning

confidence: 54%

“…However, patterns of expression of cell cycle proteins targeted by HPV E6 and E7 observed in studies of cancers from these different anatomic sites have not always supported this hypothesis, and there has even been variation between the different studies of cervical cancers. 2,9,10 Inconsistencies in p53 positivity rates in cervical as opposed to head and neck cancers can be explained by differences in the rates of p53 mutation. p53 mutations have rarely been detected in HPV-positive cervical cancers 11 but appear to coexist with HPV in some head and neck cancers.…”

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confidence: 99%

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer

Thompson

Cossart

et al. 2004

Modern Pathology

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High-risk human papillomaviruses are the causative agents of cervical cancer and are also believed to be aetiologically involved in a subset of squamous cell carcinomas of the head and neck region, especially the tonsil. Cervical cancers arise through disruption of the pathways of p53 and the product of the retinoblastoma gene by the human papillomavirus oncoproteins E6 and E7. It is generally assumed that the same pathways are involved in human papillomavirus-induced carcinogenesis at other mucosal surfaces. However, the patterns of expression of cell cycle proteins targeted by human papillomavirus E6 and E7 in cancers from different anatomic sites have been inconsistent, due to either biologic or technological factors. In this study, 73 human papillomavirus, 16-positive cervical squamous cell carcinomas (35 from Australian and 38 from Chinese women) were analysed for the expression of p53, pRb, p16 INK4A , p21 CIP1/WAF1 , p27 KIP1 and cyclin D1 by semiquantitative immunohistochemistry. Cervical cancers from Chinese women were found to be significantly more likely to overexpress p53, pRb, p21 and p27 than their Australian counterparts. These findings were compared with those from 31 human papillomavirus 16-positive tonsillar squamous cell carcinomas, all of Australian origin, tested using the same methodology. Comparisons of the tonsillar and combined cervical data showed that tonsillar cancers were significantly more likely to be p53-positive, whereas cervical cancers were significantly more likely to overexpress pRb, p16 and p27. When the tonsillar data were compared with cervical data from Australian women, the associations for p53 and pRb remained. These findings represent new evidence that the molecular pathways to human papillomavirus-induced mucosal cancer may be influenced by anatomic location and ethnicity.

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Role of cell‐cycle regulatory proteins in gynecological cancer

Cited by 48 publications

References 214 publications

Cell Cycle Genes in Ovarian Cancer

Cell Cycle Genes in Ovarian Cancer

Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer

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Role of cell‐cycle regulatory proteins in gynecological cancer

Cited by 48 publications

References 214 publications

Cell Cycle Genes in Ovarian Cancer

Cell Cycle Genes in Ovarian Cancer

Tumor suppressor p16 INK4A is necessary for survival of cervical carcinoma cell lines

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer

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Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines