Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance

Bi, Caifeng; Ye, Peng; Chen, Yeh; Liu, Tong; Cha, Jong-Ho; Yan, Xiuwen; Yang, Wen Hao

doi:10.3389/fonc.2020.01657

Cited by 12 publications

(6 citation statements)

References 181 publications

(227 reference statements)

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“…Estrogens are essential for human health and have broad biologic mechanisms of action such as regulating reproductive processes and the development and homeostasis of a wide range of tissues and organs, as well as playing a crucial role in the cardiovascular, nervous, immune systems, and bone metabolism [ 13 ]. In addition, tumor expression of hormone receptors plays an important role as an indicator of clinical prognosis of breast and genito-urinary cancers [ 14 ]. It has been reported that in patients with MPM, tumor expression levels of the estrogen receptor beta (ERβ) as assessed by immunohistochemistry (IHC) are correlated with survival [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

Rienzo

Coleman

Yeap

et al. 2021

Cancers

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Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

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Section: Introductionmentioning

confidence: 99%

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

Rienzo

Coleman

Yeap

et al. 2021

Cancers

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“…In the last decades, considerable progresses have been made in BC treatment, especially through the introduction of targeted therapies against the signaling pathways governing cancer onset and progression [ 33 – 35 ]. For instance, ER, PR and HER2 play key roles in the evolution of the majority of BCs, and selective targeting of these proteins has enabled the inhibition of their associated pathways, leading to a better prognosis for tumors that are positive for these receptors [ 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

The PTX3/TLR4 autocrine loop as a novel therapeutic target in triple negative breast cancer

Giacomini,

Turati,

Grillo

et al. 2023

Exp Hematol Oncol

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Background The pattern recognition receptor long pentraxin-3 (PTX3) plays conflicting roles in cancer by acting as an oncosuppressor or as a pro-tumor mediator depending on tumor context. Triple negative breast cancer (TNBC) represents the most aggressive histotype of breast cancer, characterized by the lack of efficacious therapeutic targets/approaches and poor prognosis. Thus, the characterization of new molecular pathways and/or alternative druggable targets is of great interest in TNBC. Methods The expression of PTX3 in BC tumor samples and in BC cell lines has been analyzed using the Gene Expression-Based Outcome for Breast Cancer Online (GOBO), qPCR, Western blot and ELISA assay. The contribution of tumor and stromal cells to PTX3 production in TNBC was assessed by analyzing single cell RNA sequencing data and RNAscope performed on TNBC tumor samples. In order to investigate the effects of PTX3 in TNBC, different cell lines were engineered to knock-down (MDA-MB-231 and BT549 cells) or overexpress (MDA-MB-468 and E0771 cells) PTX3. Finally, using these engineered cells, in vitro (including gene expression profiling and gene set enrichment analyses) and in vivo (orthotopic tumor models in immune-compromised and immune competent mice) analyses were performed to assess the role and the molecular mechanism(s) exerted by PTX3 in TNBC. Results In silico and experimental data indicate that PTX3 is mainly produced by tumor cells in TNBC and that its expression levels correlate with tumor stage. Accordingly, gene expression and in vitro results demonstrate that PTX3 overexpression confers a high aggressive/proliferative phenotype and fosters stem-like features in TNBC cells. Also, PTX3 expression induces a more tumorigenic potential when TNBC cells are grafted orthotopically in vivo. Conversely, PTX3 downregulation results in a less aggressive behavior of TNBC cells. Mechanistically, our data reveal that PTX3 drives the activation of the pro-tumorigenic Toll-like receptor 4 (TLR4) signaling pathway in TNBC, demonstrating for the first time that the PTX3/TLR4 autocrine stimulation loop contributes to TNBC aggressiveness and that TLR4 inhibition significantly impacts the growth of PTX3-producing TNBC cells. Conclusion Altogether, these data shed light on the role of tumor-produced PTX3 in TNBC and uncover the importance of the PTX3/TLR4 axis for therapeutic and prognostic exploitation in TNBC. Graphical abstract

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“…60 In addition, it has been reported that estrogen regulates the SC of the human reproductive system, which induces SC proliferation and participates in the regulation of SC populations in a paracrine manner. 61 In summary, we have analyzed the expression of SC/TSC markers at different stages of hyperplastic/adenomatous pituitary development. It was demonstrated that there was an increase in protein levels at the beginning of the tumoral process for GFRa2, Nestin, CD44 and CD133, with a different distribution of the SC/TSC niche being predominant in the adenomatous AP, probably acting as a reservoir in terms of the origin of the differentiated cells that later composed the adenoma mass.…”

Section: Discussionmentioning

confidence: 99%

Changes of stem cell niche during experimental pituitary tumor development

Guido

Sosa

Pérez

et al. 2021

J Neuroendocrinology

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To investigate the putative stem cell/tumor stem cell (SC/TSC) niche contribution to hyperplasic/adenomatous pituitary lesions, we analyzed variation in the pituitary stem cell population during the development of experimental pituitary tumors. Pituitary tumors were induced in female F344 rats with estradiol benzoate for 5, 10, 20 and 30 days. Cells positive for GFRa2, Sox2, Sox9, Nestin, CD133 and CD44 were identified in the marginal zone and in the adenoparenchyma in both control and 30D groups, with predominant adenoparenchyma localization of GRFa2 and SOX9 found in tumoral pituitaries. GFRa2, Nestin, CD133 and CD44 were upregulated at the initial stages of tumor growth, whereas Sox9 significantly decreased at 5D, with Sox2 remaining invariable during the hyperplasic/adenomatous development. In addition, isolated pituispheres from normal and tumoral pituitary glands enriched in SC/TSC were characterized. Pituispheres from the 30D glands were positive for the above-mentioned markers and showed a significant increase in the proliferation. In conclusion, our data revealed pituitary SC pool fluctuations during hyperplastic/adenomatous development, with differential localization of the SC/TSC niche in this process. These findings may help to provide a better understanding of these cell populations, which is crucial for achieving advancements in the field of pituitary tumor biology.

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Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance

Cited by 12 publications

References 181 publications

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

The PTX3/TLR4 autocrine loop as a novel therapeutic target in triple negative breast cancer

Changes of stem cell niche during experimental pituitary tumor development

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