Hormone Therapy and Ovarian Cancer

Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms; Kruger-Kjaer, Susanne; Lidegaard, Øjvind

doi:10.1001/jama.2009.1052

Cited by 205 publications

(120 citation statements)

References 15 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…A recent study suggests that metformin could lower cancer risk, reduce the rate of cancer deaths (12,13), and kill cancer cells. These effects were mainly dependent on targeting the AMPK-mTOR signaling pathway (10,14). In the present study, the results showed that metformin treatment resulted in downregulation of VEGF and Slit2 in a dose-dependent manner.…”

Section: Metformin Inhibits Lh-induced Angiogenesis By Blocking the Msupporting

confidence: 54%

See 1 more Smart Citation

Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway

Liao

Zhou

et al. 2012

Oncol Rep

View full text Add to dashboard Cite

Abstract. High levels of gonadotropin are a risk factor for ovarian cancer development. Aberrant gonadotropin levels benefit tumor angiogenesis, but the detailed mechanism is not clear. Therefore, the aim of this study was to investigate the molecular mechanism of high levels of luteinizing hormone (LH) on the promotion of tumor angiogenesis and to outline a feasible therapeutic strategy. Western blotting and immunofluorescence staining were used to determine the effect of LH on VEGF and Slit2 expression and examine the signaling pathway involved in regulating the expression of both molecules. Real-time PCR was used to investigate the effect of metformin on LH induction of VEGF and Slit2 expression. It was found that 50 mIU/ml LH significantly upregulated VEGF and Slit2 expression, and activated the PI3K/AKT-mTOR signaling pathway. However, metformin inhibited the mTOR signaling pathway and further blocked LH-induced VEGF and Slit2 expression. In conclusion, high levels of LH promote angiogenesis in ovarian cancer via the PI3K/AKT-mTOR pathway. However, metformin could inhibit tumor angiogenesis by blocking the mTOR signaling pathway. IntroductionLuteinizing hormone (LH), one of the gonadotropins, is a pituitary glycoprotein hormone that regulates ovarian steroidogenesis. The gonadotropin theory of ovarian cancer proposes that accumulated serum gonadotropins, follicle-stimulating hormone (FSH) and LH, contribute to the development of ovarian cancer. A growing body of evidence has implicated the role of LH in the etiology of ovarian epithelial cancer (OEC). Previous studies show that LH inhibits Fas-induced apoptosis in ovarian cancer and supports the hypothesis of hormonal involvement in ovarian carcinogenesis (1). In addition, it reports that LH could enhance the invasion and migration of ovarian cancer via the PI3K/AKT signaling pathway. Recent evidence suggests that gonadotropins promote ovarian cancer OV207 and OVCAR-3 cell migration and proliferation by activation of ERK1/2 signaling in a calciumand PKC δ-dependent manner (2). However, little is known about the role of LH in tumor angiogenesis.Vascular endothelial growth factor (VEGF) is a glycoprotein which is associated with tumor angiogenesis (3). Higher levels of VEGF are consistent with poor prognosis and tumor progression in various types of tumors, including ovarian cancer (4). Elevated levels of gonadotropin are risk factors for ovarian cancer and have multiple bio-activations; a study addressed the role of LH on angiogenesis in ovarian cancer. Wang et al reported that LH induced VEGF expression in AO cells in a dose-dependent manner. This study suggests that VEGF may accelerate ovarian tumor growth and tumor recurrence under elevated gonadotropin levels after menopause or surgery (5). However, the detailed mechanism of the LH-induced VEGF expression is not clear. Except of VEGF, a recent study indicates that Slit2, a secreted protein known to function through the Roundabout (Robo) receptor as a chemorepellent in axon guidance and neuronal migration...

show abstract

Section: Metformin Inhibits Lh-induced Angiogenesis By Blocking the Msupporting

confidence: 54%

“…Increasing evidence suggests that the hormone environment is an important factor for cancer development, especially in ovarian cancer (8,11,(14)(15)(16). These hormones, including gonadotropin, gonadotropin releasing hormone and progestin, often play multiple roles; they commonly regulate cellular growth, cell migration and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway

Liao

Zhou

et al. 2012

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Hormone replacement therapy has been shown to increase the risk of developing ovarian cancer in post-menopausal women; oestrogen-only therapy increased risk by 22% and the combined oestrogen and progesterone therapy increased risk by 10% (33)(34)(35). However, a meta-analysis showed a similar increase in the risk of developing ovarian cancer, specifically, serous and endometrioid carcinomas, in menopausal women using hormone replacement therapy, regardless of whether the therapy contained only oestrogen or a combination of oestrogen and progesterone (36).…”

Section: [H2] Risk Factorsmentioning

confidence: 99%

Ovarian cancer

Matulonis

Sood

Fallowfield

et al. 2016

Nat Rev Dis Primers

938

787

View full text Add to dashboard Cite

Ovarian cancer is not a single disease and can be subdivided into at least five different 2 histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at late stage, and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents, and poly (ADP ribose) polymerase (PARP) inhibitors are used and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and is typically very responsive to platinum-based chemotherapy at diagnosis. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy.Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Significant progress has been made in identifying genes associated with high risk of ovarian cancer (such as BRCA1 and BRCA2) as well as a precursor lesion of HGSC called a serous tubal intraepithelial carcinoma, which hold promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. Competing interestsU.A.M. has served as a consultant for AstraZeneca, ImmunoGen, Pfizer, Genentech, and Merck.

show abstract

“…9,10 Since 1968, all citizens in Denmark have had personal identification numbers recorded in the Civil Registration System, which also records the dates of birth, immigration, emigration and death, as well as actual residence. The personal identification number allows reliable linkage between different national registries for scientific purposes.…”

Section: Data Collectionmentioning

confidence: 99%

The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study

Mørch

Kjær

Keiding

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

The influence of hormone therapy (HT) on risk for endometrial cancer is still casting which type of HT the clinicians recommend. It is unrevealed if HT has a differential influence on Type I versus Type II endometrial tumors, and little is known about the influence of, e.g., different routes of administration and about the influence of tibolone. We followed all Danish women aged 50-79 years without previous cancer or hysterectomy (n 5 914,595) during 1995-2009. From the National Prescription Register, we computed HT exposures as time-dependent covariates. Incident endometrial cancers (n 5 6,202) were identified from the National Cancer Registry: 4,972 Type I tumors and 500 Type II tumors. Incidence rate ratios (RRs) and 95% confidence intervals (Cls) were estimated by Poisson regression. Compared with women never on HT, the RR of endometrial cancer was increased with conjugated estrogen: 4.27 (1.92-9.52), nonconjugated estrogen: 2.00 (1.87-2.13), long cycle combined therapy: 2.89 (2.27-3.67), cyclic combined therapy: 2.06 (1.88-2.27), tibolone 3.56 (2.94-4.32), transdermal estrogen: 2.77 (2.12-3.62) and vaginal estrogen: 1.96 (1.77-2.17), but not with continuous combined therapy: 1.02 (0.87-1.20). In contrast, the risk of Type II tumors appeared decreased with continuous combined therapy: 0.45 (0.20-1.01), and estrogen therapy implied a nonsignificantly altered risk of 1.43 (0.85-2.41). Our findings support that continuous combined therapy is risk free for Type I tumors, while all other hormone therapies increase risk. In contrast, Type II endometrial cancer was less convincingly associated with hormone use, and continuous combined therapy appeared to decrease the risk.Use of unopposed estrogen therapy (ET) is known to increase the risk of endometrial cancer.1 As a result, it is standard to prescribe combined estrogen-progestin therapy (EPT) to counteract the proliferative effects on the endometrium of estrogen. Some studies suggest cyclic EPT to increase the risk of endometrial cancer while continuous EPT should be risk free.

show abstract

Hormone Therapy and Ovarian Cancer

Cited by 205 publications

References 15 publications

Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway

Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway

Ovarian cancer

The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study

Contact Info

Product

Resources

About