Endometrial Carcinoma: Specific Targeted Pathways

Eritja, Núria; Yeramian, Andrée; Chen, Bo-Juen; Llobet‐Navas, David; Ortega, Eugenia; Colás, Eva; Abal, Miguel; Dolcet, Xavier; Reventós, Jaume; Matías‐Guiu, Xavier

doi:10.1007/978-3-319-43139-0_6

Cited by 52 publications

(38 citation statements)

References 342 publications

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“…As reported, cancerous human endometrium expresses lower levels of TGFBR1 protein [47,52]. TGFBR2 is mutated/altered in 6.5% of endometrial tumours [49,51]. Studies from The Cancer Genome Atlas Research Network have also suggested alterations of several SMADs in human endometrial cancer [49,51].…”

Section: Discussionmentioning

confidence: 94%

“…It has been shown that mutations of TGFB signalling components, including TGFB receptors and SMADs, and alteration of TGFB signalling activity reflected by changes in gene expression and/or phosphorylation of key signalling proteins play a role in the patho-aetiology of human endometrial cancer [47,49,50]. TGFBR1 has a 5.6% mutation and alteration rate in human endometrial cancer [49,51]. As reported, cancerous human endometrium expresses lower levels of TGFBR1 protein [47,52].…”

Section: Discussionmentioning

confidence: 99%

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Conditional abrogation of transforming growth factor‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

Gao

Lin

Lydon

et al. 2017

The Journal of Pathology

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Although a putative role for TGF beta (TGFB) signaling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signaling in the development and progression of endometrial cancer remains elusive. Depletion of PTEN in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signaling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus using Cre-recombinase driven by the progesterone receptor (termed Ptend/d; Tgfbr1d/d). We found that Ptend/d; Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly compared with those resulting from conditional deletion of Pten alone, suggesting that TGFB signaling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, the Ptend/d; Tgfbr1d/d mice developed distant pulmonary metastases, leading to significantly reduced life span. The development of metastasis and accelerated tumor progression in Ptend/d; Tgfbr1d/d mice are associated with increased production of pro-inflammatory chemokines, enhanced cancer cell motility evidenced by myometrial invasion and disruption, and altered tumor microenvironment characterized by recruitment of tumor-associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN-inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Conditional abrogation of transforming growth factor‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

Gao

Lin

Lydon

et al. 2017

The Journal of Pathology

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“…Among its targets, AKT phosphorylates and inhibits tuberous sclerosis complex 2 (TSC2) within the TSC complex, which indirectly inhibits mTOR complex 1 (mTORC1). PI3K-AKT signaling activates mTORC1 [ 56 ], a key regulator of metabolism and biosynthetic processes, including activation of hypoxia-inducible factor 1 (HIF1) and other transcription factors. HIF1 stimulates glucose transporter expression on the cell surface, thereby increasing cellular glucose influx, and shifts metabolic pathways towards glycolysis through inhibitory mitochondrial pyruvate dehydrogenase kinase activation [ 49 , 57 ].…”

Section: Reviewmentioning

confidence: 99%

New therapies for advanced, recurrent, and metastatic endometrial cancers

Makker

Green

Wenham

et al. 2017

gynaecol oncol res pract

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Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were diagnosed with endometrial cancer, and approximately 11,000 died from this disease. From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths. Although there are many chemotherapeutic and targeted therapy agents approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration (FDA)-approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer; this highlights the need for new therapies to treat advanced, recurrent, metastatic endometrial cancer. In this review, we discuss current and emerging treatment options for endometrial cancer, including chemotherapy, targeted therapy, and immunotherapy. The National Cancer Institute (NCI) and others are now focusing their efforts on the design of scientifically rational targeted therapy and immunotherapy trials for specific molecular phenotypes of endometrial cancer. This is essential for the advancement of cancer care for women, which is threatened by a severe enrollment decline of approximately 80% for gynecologic oncology clinical trials.

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“…A number of previous reviews have discussed signalling pathways involved in homeostasis of the endometrium and various pathologies, and two recent reviews have examined Wnt inhibitors in pre-clinical settings but with limited discussion of implications for endometrial cancer (Eritja et al 2017, Katoh & Katoh 2017. Previous reviews have focused on β-catenin-dependent Wnt signalling with no discussion of the β-catenin-independent receptors Classification Historically, endometrial cancer was classified into two distinct subtypes known as Bokhman type one and type two (Bokhman 1983).…”

Section: Introductionmentioning

confidence: 99%

An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

Coopes

Henry

Llamosas

et al. 2018

Endocrine-Related Cancer

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Endometrial cancer is the most common gynaecological malignancy in developed nations, and its prevalence is rising as women defer or decide not to have children and as obesity rises, both key risk factors. Despite this, treatment options remain limited, particularly for advanced or refractory disease. New genomic analyses have revealed distinct mutational profiles with therapeutic and prognostic potential. Wnt signalling, which is pivotal in embryogenesis, healing and homeostasis, is of importance in the endometrium and has been linked to carcinogenesis. This review aims to update and discuss the current evidence for the role of β-catenin dependent and independent Wnt signalling, including the ROR receptors in the endometrium and its potential as a therapeutic target, in light of recent trials of Wnt-targeted therapy in multiple tumour types.

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Endometrial Carcinoma: Specific Targeted Pathways

Cited by 52 publications

References 342 publications

Conditional abrogation of transforming growth factor‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

Conditional abrogation of transforming growth factor‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

New therapies for advanced, recurrent, and metastatic endometrial cancers

An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

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