Reduced PAX2 expression in murine fallopian tube cells enhances estrogen receptor signaling

Colina, Jose A.; Varughese, Peter; Karthikeyan, Subbulakshmi; Salvi, Amrita; Modi, Dimple; Burdette, Joanna E.

doi:10.1093/carcin/bgz127

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…6B, C ) . These data are consistent with the literature where loss of PAX2 increased the CSC marker CD44 28 and increased ALDH 29 . Overexpression of PAX2 in SCR shRNA , which already express endogenous PAX2, did not alter mRNA expression of the CSC markers ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

et al. 2021

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High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.

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Section: Resultssupporting

confidence: 93%

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

et al. 2021

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“…On day of collection, media was removed, and cells were fixed with 20% trichloroacetic acid (TCA). Proliferation was measured by sulforhodamine B (SRB) as previously described [30]. Fold proliferation values were normalized to day 0.…”

Section: Proliferation Assaymentioning

confidence: 99%

Baicalein Is a Phytohormone that Signals Through the Progesterone and Glucocorticoid Receptors

et al. 2020

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While flavonoids have been studied extensively for estrogen receptor activity, they have not been well studied for their ability to modify progesterone receptor (PR) and glucocorticoid receptor (GR) signaling. Three flavonoid compounds, tangeretin, wogonin, and baicalein, were selected for testing for PR and GR activity based on their structural similarity to known phytoprogesterone-like compounds. Each compound was docked in the binding pocket of PR and GR. Of these compounds, baicalein was predicted to be most likely to bind to both receptors. A fluorescence polarization competitive binding assay for PR and GR confirmed that baicalein binds to both the PR and GR with IC 50 values of 15.30 μM and 19.26 μM, respectively. In Ishikawa PR-B and T47D cells, baicalein acted as a PR antagonist in a hormone response element (HRE) luciferase (Luc) assay. In OVCAR5 cells, which only express GR, baicalein was a GR agonist via an HRE/Luc assay and induced GR target genes, FKBP5 and GILZ. RU486, a PR and GR antagonist, abrogated baicalein's activity in OVCAR5 cells, confirming baicalein's activity is mediated through the GR. In vivo, baicalein administered intraperitoneally to female mice twice a week for 4 weeks at a dose of 25 mg/kg induced the GR target gene GILZ in the reproductive tract, which was blocked by RU486. In summary, baicalein has PR antagonist and GR agonist activity in vitro and demonstrates GR agonist activity in the uterus in vivo.

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“…One of the risk factors of HGSOC is elevated estrogen exposure and 80% of HGSOCs have been shown to express estrogen receptor (ER) ( 24 ). PAX2 reduction has been associated with increased responsiveness of the ER to estrogen, further supporting the idea that SCOUTs may be precursor lesions of HGSOC ( 22 ). Estrogen has been shown to induce tumor formation through the activation of proliferation signaling pathways.…”

Section: Microenvironment At the Site Of Originmentioning

confidence: 56%

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Ritch

Telleria

2022

Front. Endocrinol.

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Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

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Reduced PAX2 expression in murine fallopian tube cells enhances estrogen receptor signaling

Cited by 9 publications

References 44 publications

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

Baicalein Is a Phytohormone that Signals Through the Progesterone and Glucocorticoid Receptors

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

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