Invasion and increased expression of S100A4 and CYR61 in mesenchymal transformed breast cancer cells is downregulated by GnRH

Gründker, Carsten; Bauerschmitz, Gerd; Schubert, Antje; Emons, Günter

doi:10.3892/ijo.2016.3491

Cited by 16 publications

(33 citation statements)

References 47 publications

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“…About 50–64% of human breast cancers have high-affinity GnRH receptors, according to various studies ( 16 – 19 ). A more recent study reported that GnRH receptor expression was detected in 67% of hyperplasia cases (4 out of 6), in 100%of benign fibroadenoma cases (3 out of 3), in 100% of carcinoma in situ cases (4 out of 4), and in 71% cases of malignant breast cancers (22 out of 31) ( 20 ). The therapeutic options today are incredibly limited in particular for triple-negative breast cancers (TNBCs), which do not exhibit either the estrogen receptor α (ERα) or the progesterone receptor and do not overexpress the HER2-neu gene.…”

Section: Expression Of Gonadotropin-releasing Hormone (Gnrh) and Its mentioning

confidence: 99%

“…The S100 calcium-binding protein A4 (S100A4) and the cysteine-rich angiogenic inducer 61 (CYR61, CCN1) promote cancer cell motility and thus play important roles in EMT, invasion, and metastasis ( 64 – 68 ). Highly invasive MDA-MB-231 breast cancer cells exhibit high expression of both genes ( 20 ). An increased CYR61 level correlates with a poor prognosis, poor lymph node status, and metastatic propagation ( 69 , 70 ).…”

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

“…High levels of S100A4 and CYR61 were found in biopsy specimens of malignant human breast cancers, whereas in carcinoma, in situ , the expression levels were much lower. No expression of S100A4 and CYR61 was detectable in normal breast tissues and benign fibroadenoma ( 20 ). MCF-7 cells are non-invasive and show very low levels of S100A4 and CYR61 expression ( 20 ).…”

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

“…No expression of S100A4 and CYR61 was detectable in normal breast tissues and benign fibroadenoma ( 20 ). MCF-7 cells are non-invasive and show very low levels of S100A4 and CYR61 expression ( 20 ). Invasion of cells and levels of S100A4 and CYR61 expression in MCF-7 cells was markedly increased after mesenchymal transition (MCF-7-EMT) ( 20 ).…”

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

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The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

2017

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In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation. The expression of GnRH receptor has also been identified in breast cancers and non-reproductive cancers such as pancreatic cancers and glioblastoma. Various investigators have observed dose- and time-dependent growth inhibitory effects of GnRH agonists in cell lines derived from these cancers. GnRH antagonists have also shown marked growth inhibitory effects on most cancer cell lines. This indicates that in the GnRH system in cancer cells, there may not be a dichotomy between GnRH agonists and antagonists. The well-known signaling mechanisms of the GnRH receptor, which are present in pituitary gonadotrophs, are not involved in forwarding the antiproliferative effects of GnRH analogs in cancer cells. Instead, the GnRH receptor activates a phosphotyrosine phosphatase (PTP) and counteracts with the mitogenic signal transduction of growth factor receptors, which results in a reduction of cancer cell proliferation. The PTP activation, which is induced by GnRH, also inhibits G-protein-coupled estrogen receptor 1 (GPER), which is a membrane-bound receptor for estrogens. GPER plays an important role in breast cancers, which do not express the estrogen receptor α (ERα). In metastatic breast, ovarian, and endometrial cancer cells, GnRH reduces cell invasion in vitro, metastasis in vivo, and the increased expression of S100A4 and CYR61. All of these factors play important roles in epithelial–mesenchymal transition. This review will summarize the present state of knowledge about the GnRH receptor and its signaling in human cancers.

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Section: Expression Of Gonadotropin-releasing Hormone (Gnrh) and Its mentioning

confidence: 99%

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

Section: Antimetastatic Action Of Gnrh In Human Cancersmentioning

confidence: 99%

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The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

2017

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“…Both endogenous and extracellular S100A4 have been linked to metastasis. Endogenous S100A4 is known to enhanced cell motility and invasion (Grundker et al ., 2016), while extracellular, stromal S100A4 has been shown to instigate inflammatory events promoting metastasis (Hansen et al ., 2014). …”

Section: Introductionmentioning

confidence: 99%

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

et al. 2018

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The tumor microenvironment (TME) may influence both cancer progression and therapeutic response. In breast cancer, particularly in the aggressive triple‐negative/basal‐like subgroup, patient outcome is strongly associated with the tumor's inflammatory profile. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the TME, shown to be linked to poor prognosis and therapeutic resistance. In this study, we investigated the effect of the metastasis‐ and inflammation‐associated microenvironmental factor S100A4 on breast cancer cells (BCCs) of different subtypes and explored their further interactions with myeloid cells. We demonstrated that extracellular S100A4 activates BCCs, particularly the basal‐like subtype, to elevate secretion of pro‐inflammatory cytokines. The secreted factors promoted conversion of monocytes to TAM‐like cells that exhibited protumorigenic activities: stimulated epithelial–mesenchymal transition, proliferation, chemoresistance, and motility in cancer cells. In conclusion, we have shown that extracellular S100A4 instigates a tumor‐supportive microenvironment, involving a network of cytokines and TAM‐like cells, which was particularly characteristic for basal‐like BCCs and potentiated their aggressive properties. The S100A4–BCC–TAM interaction cascade could be an important contributor to the aggressive behavior of this subtype and should be further explored for therapeutic targeting.

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Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins

Ramírez‐Expósito

Martínez-Martos

Dueñas

et al. 2020

Breast Cancer Res Treat

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Invasion and increased expression of S100A4 and CYR61 in mesenchymal transformed breast cancer cells is downregulated by GnRH

Cited by 16 publications

References 47 publications

The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins

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