Progesterone: the ultimate endometrial tumor suppressor

Yang, Shujie; Thiel, Kristina W.; Leslie, Kimberly K.

doi:10.1016/j.tem.2011.01.005

Cited by 160 publications

(146 citation statements)

References 84 publications

(111 reference statements)

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“…treatment side-effects; falsepositive screening diagnoses) (11). With regard to EC, one conceivable type of chemopreventive treatment is the use of progestins (7,8,10) in the form of combined OC (25), or progestin-based alternatives such as a depot of medroxyprogesterone acetate (MPA) (26) or a levonorgestrelreleasing intra-uterine system (LNG-IUS) (27).…”

Section: Discussionmentioning

confidence: 99%

“…Information on a woman's risk of developing EC within the next five years derived from valid risk models can help physicians to motivate or proactively propose targeted clinical prevention measures such as the preventive use of progestin-based hormonal treatments (10). Risk models may help balance expected benefits against possible harms of preventive treatments and can also be a useful tool for selecting women who may benefit from screening programs (11,12).…”

Section: Introductionmentioning

confidence: 99%

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An epidemiological model for prediction of endometrial cancer risk in Europe

et al. 2015

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Endometrial cancer is the fourth most frequent cancer in women in Europe, and as its incidence is increasing, prevention strategies gain further pertinence. Risk prediction models can be a useful tool for identifying women likely to benefit from targeted prevention measures. On the basis of data from 201,811 women (mostly aged 30-65 years) including 855 incident endometrial cancer cases from eight countries in the European Prospective Investigation into Cancer and Nutrition cohort, a model to predict endometrial cancer (EC) was developed. A step-wise model selection process was used to select confirmed predictive epidemiologic risk factors. Piece-wise constant hazard rates in 5-year age-intervals were estimated in a cause-specific competing risks model, five-fold-cross-validation was applied for internal validation.Risk factors included in the risk prediction model were body-mass index (BMI), menopausal status, age at menarche and at menopause, oral contraceptive use, overall and by different BMI categories and overall duration of use, parity, age at first full-term pregnancy, duration of menopausal hormone therapy and smoking status (specific for pre, peri-and post-menopausal women). These variables improved the discriminating capacity to predict risk over 5 years from 71% for a model based on age alone to 77% (overall C statistic), and the model was wellcalibrated (ratio of expected to observed cases = 0.99).Our model could be used for the identification of women at increased risk of EC in Western Europe. To achieve an EC-risk model with general validity, a large-scale cohort-consortium approach would be needed to assess and adjust for population variation. Husing_EndometrCaRiskmodel_EurJEpidemiol_2015_authorversion4

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An epidemiological model for prediction of endometrial cancer risk in Europe

et al. 2015

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“…Progesterone has been long known as a crucial antagonist of EC progression through a variety of mechanisms, notably through cell cycle arrest and apoptosis induction (Yang et al 2011). However, progestin resistance is a major hurdle in the treatment of EC.…”

Section: Cancermentioning

confidence: 99%

Expression, activation, and role of AKT isoforms in the uterus

Fabi¹,

Asselin²

2014

Reproduction

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The three isoforms of AKT: AKT1, AKT2, and AKT3, are crucial regulators of both normal and pathological cellular processes. Each of these isoforms exhibits a high level of homology and functional redundancy with each other. However, while being highly similar and structurally homologous, a rising amount of evidence is showing that each isoform possesses specific targets as well as preferential subcellular localization. The role of AKT has been studied extensively in reproductive processes, but isoform-specific roles are yet to be fully understood. This review will focus on the role of AKT in the uterus and its function in processes related to cell death and proliferation such as embryo implantation, decidualization, endometriosis, and endometrial cancer in an isoform-centric manner. In this review, we will cover the activation of AKT in various settings, localization of isoforms in subcellular compartments, and the effect of isoform expression on cellular processes. To fully understand the dynamic molecular processes taking place in the uterus, it is crucial that we better understand the physiological role of AKT isoforms as well as their function in the emergence of diseases.Reproduction (2014) 148 R85-R95

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“…Progesterone resistance is a complex process; the change in ER and PR did not inhibit the stimulatory effects of MPA on the progestin-resistant cells. A compensatory pathway may therefore exist to support proliferation over long-term MPA treatment (19)(20)(21)(22)(23)(24)(25). This requires further study.…”

Section: Discussionmentioning

confidence: 99%

Response-specific progestin resistance in a newly characterized Ishikawa human endometrial cancer subcell line resulting from long-term exposure to medroxyprogesterone acetate

Zhao

et al. 2012

Oncology Letters

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Abstract. Progestins, particularly medroxyprogesterone acetate (MPA), have for a long time been used as conservative treatment for young patients with clinical stage I, grade I endometrial carcinoma. However, more than 30% of patients with endometrial adenocarcinoma display resistance to endocrine therapies at the time of presentation and most cancer patients that initially respond to progestin treatment will at some point develop resistance, resulting in tumor progression. The cellular mechanisms underlying acquired resistance to progestin are poorly understood. In order to investigate the molecular mechanisms whereby human endometrial adenocarcinoma develops resistance to progestin therapy, we have undertaken to develop human endometrial adenocarcinoma cell lines that are resistant to the growth-inhibitory effects of progestins in vitro. A progestin-resistant subcell line of Ishikawa cells was developed from Ishikawa human endometrial adenocarcinoma cells by stepwise selection in increasing concentrations of the synthetic progestin, MPA, over ten months. The doubling time of the progestin-resistant cells (34.18±3.15 h) grown routinely in the medium containing 10 µM MPA was not significantly different from the doubling time of the parent Ishikawa cells (35.14±2.68 h) grown in the absence of MPA (t=-0.331, P=0.762). Moreover, the effect of treatment with MPA shifted from suppression of growth and invasiveness, as observed in the parent Ishikawa cells, to stimulation of growth and invasiveness in the progestin-resistant Ishikawa cells. The positive rates of estrogen receptor a (ERα) and progesterone receptor B (PRB) of the progestin-resistant Ishikawa cells were significantly reduced, whilst the positive rate of ERβ was significantly enhanced compared to the parent Ishikawa cells. These differences were statistically significant (P<0.05). Our results indicate that long-term treatment with MPA in Ishikawa cells may give rise to a resistance effect to MPA. When the resistant subtype is acquired, treatment with MPA enhances cancer cell proliferation and invasiveness. The imbalance of ER and PR subtypes may contribute to the mechanisms involved in progestin resistance. Determination of the subtypes of ER and PR may provide important additional information on the hormone sensitivity of endometrial carcinoma.

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Progesterone: the ultimate endometrial tumor suppressor

Cited by 160 publications

References 84 publications

An epidemiological model for prediction of endometrial cancer risk in Europe

An epidemiological model for prediction of endometrial cancer risk in Europe

Expression, activation, and role of AKT isoforms in the uterus

Response-specific progestin resistance in a newly characterized Ishikawa human endometrial cancer subcell line resulting from long-term exposure to medroxyprogesterone acetate

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