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• W2022809018 abstract "Increasing epidemiological evidence suggests a role of steroid hormones in the development and progression of certain molecular subtypes of ovarian cancer. In general, the data suggest that estrogens are associated with increased risk of ovarian cancer, while progesterone and progestins may have a protective role (for recent review on this topic, see ref. 1). Despite these epidemiological associations, there remains a surprisingly limited understanding of the underlying biology and mechanisms of steroid receptor action in early and late stages of ovarian tumorigenesis. However, given that hormonal therapies represent the best of “targeted therapy in personalized medicine,” with limited toxicities, there is renewed interest in the static and maintenance roles for hormonal therapy in ovarian cancer recurrence. In addition, there might be a role for endocrine therapy in treatment of early-stage ovarian cancer, when expression of nuclear receptors is high.In the May 1, 2013 issue of Cell Cycle, Carol Lange and colleagues published an exciting study, which provides mechanistic insight into how progesterone receptor (PR) mediates the protective effects of progestins in ovarian cancer.2 The authors used a number of established ovarian cancer cell lines of different histological subtypes to show that progestins activate nuclear PR, leading to elevated FOXO1 expression and ultimately cellular senescence. Senescence is at least in part due to the induction of the cell cycle inhibitor p21. It is important to point out that in addition to the elegant mechanistic studies, the authors provide very valuable and extensive data on PR protein expression in the different molecular subtypes of human ovarian cancer, showing low PR expression in clear cell and mucinous tumors (3 and 18%, respectively) and moderate to high expression in serous (35%), low-grade serous (64%) and endometriod tumors (67%) (Fig. 1).Figure 1. Schematic representation of PR action as target in different subtypes of ovarian cancer. SMS, senescence messaging secretome.As with other scientific studies, this manuscript provides clues to mechanism of action of progestins but at the same time raises many new questions. For example, what is the cause for the biphasic dose response to progestins? Does this imply a critical role for the other progesterone-binding proteins? And can this explain prior discrepant results showing both progesterone-induced apoptosis and proliferation? Importantly, given the increasing realization of diverse roles of the two PR isoforms, PR-A and PR-B, what can we expect to see from loss (or overexpression) of the PR-A isoform? And, finally, what is the role of PR action in the tumor microenvironment?This study has important translational implications, in that PR agonists (and antagonists) are clinically available. However, to date, small clinical trial cohorts have demonstrated modest activity in ovarian cancer.3 Many of these trials have limitations, and it might be time to revisit the potential use of progestins and anti-progestins in ovarian cancer therapy. Several steps can be taken. First and foremost is the need to use biomarkers to predict active PR signaling in the tumor (and possibly the stroma). In addition, clinical trials mostly occurred in chemotherapy-resistant, late-stage disease; however, data at hand suggest that there is progressive loss of PR during tumor progression. This might imply a place for progestin in early-stage tumorigenesis, perhaps from precursors like endometriosis, which predispose to endometrioid, clear cell and low-grade serous ovarian tumors (Fig. 1). In support of this rationale is the fact that PR expression is highest in low-grade serous and endometrioid (although not clear cell) tumors,2,4 further suggesting the early roles of PR-mediated pathogenesis and the potential for PR-targeted therapy or prevention, at least in some histological subtypes. And finally, the idea of using synthetic lethal approaches, i.e., combining progestin with drugs showing increased efficacy against senescent cells would be warranted. One approach that comes to mind is the use of immune therapies. Senescence of epithelial tumor cells leads to the release of inflammatory proteins and mediators of extracellular matrix (also called the senescence- messaging secretome or SMS),5,6 which can act as activators of the innate immune response, leading to tumor cell clearance. In addition, active immunization with senescent cell-derived, tumor antigen-based vaccines may act in synergy to the potentially immunogenic in vivo inducers of senescence (like progestins, for example), providing additional benefits in both therapeutic as well as preventive approaches, although the efficacy of such approaches remains to be determined.In summary, a renewed effort to understand steroid hormone action in ovarian cancer (in both the epithelium and stroma) may lead to novel approaches for targeted therapies with limited toxicities and therapeutic benefit." @default.
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• W2022809018 date "2013-06-01" @default.
• W2022809018 modified "2023-09-30" @default.
• W2022809018 title "Progestins: Pro-senescence therapy for ovarian cancer?" @default.
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• W2022809018 doi "https://doi.org/10.4161/cc.25072" @default.
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