2-Methoxyestradiol Inhibits Progesterone-Dependent Tissue Factor Expression and Activity in Breast Cancer Cells

Quezada, Maribel; Díaz, Jorge; Henríquez, Sandra; Bravo, María Loreto; Aranda, Evelyn; Oliva, Bárbara; Villalón, Manuel; Kato, Sumie; Cuello, Mauricio; Brosens, Jan J.; Lange, Carol A.; Owen, Gareth I.

doi:10.1007/s12672-010-0019-5

Cited by 10 publications

(8 citation statements)

References 53 publications

(63 reference statements)

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“…Although this is not the first observation that progesterone can regulate PAR1, this is, to our knowledge, the first to demonstrate regulation in breast cancer or mammary glandderived cells. It has not escaped our notice that the timing and mechanism of PAR1 regulation by progesterone is remarkably similar to the progesterone regulation of TF in both T47D and ZR-75 cells (Kato et al 2005b, Quezada et al 2010, Henriquez et al 2011. Advanced breast cancer is associated with a hypercoagulable state that may be triggered or enhanced by the presence of TF and PAR1 on the surface of cancer cells (Ruf & Mueller 2006).…”

Section: Discussionmentioning

confidence: 93%

Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

Díaz¹,

Aranda²,

Henríquez³

et al. 2012

Journal of Endocrinology

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Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3 h and returning to basal levels at 18 h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women.

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Section: Discussionmentioning

confidence: 93%

Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

Díaz¹,

Aranda²,

Henríquez³

et al. 2012

Journal of Endocrinology

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“…Furthermore, 2-ME impacts on various physiological and pathological conditions like muscle contraction or pre-eclampsia [18,31,32,34]. Studies in vitro and in vivo revealed that 2-ME at pharmacological concentrations inhibited the growth of various cancer types, including colon [35], breast [36], or lung [37]. On the contrary, there are only a few data concerning physiological activity of 2-ME [17,38].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

et al. 2015

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2-methoxyestradiol, metabolite of 17β-estradiol, is considered a potential anticancer agent, currently investigated in several clinical trials. This natural compound was found to be effective towards great number of cancers, including colon, breast, lung, and osteosarcoma and has been reported to be relatively non-toxic towards non-malignant cells. The aim of the study was to determine the potential neurotoxicity and genotoxicity of 2-methoxyestradiol at physiological and pharmacological relevant concentrations in hippocampal HT22 cell line. Herein, we determined influence of 2-methoxyestradiol on proliferation, inhibition of cell cycle, induction of apoptosis, and DNA damage in the HT22 cells. The study was performed using imaging cytometry and comet assay techniques. Herein, we demonstrated that 2-methoxyestradiol, at pharmacologically and also physiologically relevant concentrations, increases nuclear localization of neuronal nitric oxide synthase. It potentially results in DNA strand breaks and increases in genomic instability in hippocampal HT22 cell line. Thus, we are postulating that naturally occurring 2-methoxyestradiol may be considered a physiological modulator of neuron survival.

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“…Anticancer activity of 2‐ME was also determined in various experimental models in vitro. 2‐ME was reported to be an effective chemotherapeutic towards colon, kidney, pancreas, breast, lung, and osteosarcoma cells (Gorska et al, , ; Maran et al, , ; Matei et al, ; Quezada et al, ; Schumacher & Neuhaus, ; Snoeks, Mol, Que, Kaijzel, & Loewik, ; Zou et al, ). Previously, we have evidenced that 2‐ME may be a physiological anticancer agent (Gorska et al, ).…”

Section: Introductionmentioning

confidence: 99%

2‐methoxyestradiol impacts on amino acids‐mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor

Górska‐Ponikowska

Perricone

Kuban–Jankowska

et al. 2017

Journal Cellular Physiology

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Deregulation of serine and glycine metabolism, have been identified to function as metabolic regulators in supporting tumor cell growth. The role of serine and glycine in regulation of cancer cell proliferation is complicated, dependent on concentrations of amino acids and tissue-specific. D-serine and glycine are coagonists of N-methyl-D-aspartate (NMDA) receptor subunit GRIN1. Importantly, NMDA receptors are widely expressed in cancer cells and play an important role in regulation of cell death, proliferation, and metabolism of numerous malignancies. The aim of the present work was to associate the metabolism of glycine and D-serine with the anticancer activity of 2-methoxyestradiol. 2-methoxyestradiol is a potent anticancer agent but also a physiological 17β- estradiol metabolite. In the study we have chosen two malignant cell lines expressing functional NMDA receptors, that is osteosarcoma 143B and breast cancer MCF7. We used MTS assay, migration assay, flow cytometric analyses, Western blotting and immunoprecipitation techniques as well as molecular modeling studies. We have demonstrated the extensive crosstalk between the deregulated metabolic network and cancer cell signaling. Herein, we observed an anticancer effect of high concentrations of glycine and D-serine in osteosarcoma cells. In contrast, the amino acids when used at low, physiological concentrations induced the proliferation and migration of osteosarcoma cells. Importantly, the pro-cancergogenic effects of both glycine and D-serine where abrogated by the usage of 2-methoxyestradiol at both physiological and pharmacological relevant concentrations. The obtained data confirmed that 2-methoxyestradiol may be a physiological anticancer molecule.

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2-Methoxyestradiol Inhibits Progesterone-Dependent Tissue Factor Expression and Activity in Breast Cancer Cells

Cited by 10 publications

References 53 publications

Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

2‐methoxyestradiol impacts on amino acids‐mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor

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