Progesterone Increases Tissue Factor Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer Cell Line ZR-75-1

Kato, Sumie; Pinto, Mauricio P.; Carvajal, Ana María; Espinoza, Natalia; Monso, C; Sadarangani, Anil; Villalón, Manuel; Brosens, Jan J.; White, John O.; Richer, Jennifer K.; Horwitz, Kathryn B.; Owen, Gareth I.

doi:10.1210/jc.2004-0857

Cited by 52 publications

(55 citation statements)

References 41 publications

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“…As potential mechanistic explanations, a number of studies reported that progesterone may enhance the invasiveness of breast cancer cells by increasing tissue factor or vascular endothelial growth factor expression (Hyder et al 2001, Kato et al 2005, or augmenting matrix metalloproteinases and urokinase-type plasminogen activator activities (Carnevale et al 2007). Nevertheless, the effects of progesterone on breast cancer cell movement or invasion remain to date poorly characterized.…”

Section: Discussionmentioning

confidence: 99%

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Goglia²,

Sanchez³

et al. 2010

Endocrine-Related Cancer

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While progesterone plays multiple roles in the process of breast development and differentiation, its role in breast cancer is less understood. We have shown previously that progestins stimulate breast cancer cell migration and invasion because of the activation of rapid signaling cascades leading to modifications in the actin cytoskeleton and cell membrane that are required for cell movement. In this study, we have investigated the effects of progesterone on the formation of focal adhesion (FA) complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances FA kinase (FAK) phosphorylation at Tyr 397 in a time-and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of FA complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3-kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell movement and invasion by facilitating the formation of FA complexes via the rapid regulation of FAK. These results provide novel mechanistic views on the effects of progesterone on breast cancer progression, and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers.

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Section: Discussionmentioning

confidence: 99%

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Goglia²,

Sanchez³

et al. 2010

Endocrine-Related Cancer

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“…In contrast, increased expression of endogenous TF (7,8) or elevated levels of TF in the tumor stroma of breast cancers has been correlated with a progression to invasive forms of the disease (5, 6, 15). In our study, supplementation of estradiol with rTF (13 pg/mL) resulted in the reversal of the anti-invasive effect of estradiol in MCF-7 cells and also increased T47D invasiveness compared with T47D cells treated with estradiol alone (Fig.…”

Section: Mol Cancer Res 2008;6(12) December 2008mentioning

confidence: 99%

“…TF, the principal initiator of the blood coagulation cascade, has been implicated in various cellular processes including cell proliferation, migration, and tumor metastasis (7,8) through its ability to initiate the activation of cell signaling pathways. High levels of TF expression in breast cancers have been associated with an elevated metastatic potential and a higher tumor grade (6,9,10), and the overexpression of TF in normally noninvasive breast tumor cells has been shown to result in increased cell invasiveness in vitro (7). In addition to the TF expressed by tumor cells, other cell types present in the tumor stroma such as vascular endothelial cells, fibroblasts, and infiltrating macrophages express increased levels of TF in invasive forms of breast cancer (5,6).…”

Section: Introductionmentioning

confidence: 99%

Influence of Exogenous Tissue Factor on Estrogen Receptorα Expression in Breast Cancer Cells: Involvement of β1-Integrin, PAR2, and Mitogen-Activated Protein Kinase Activation

Collier

Ettelaie

2008

Molecular Cancer Research

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Increased expression of tissue factor (TF) has been associated with invasive forms of breast cancer. Conversely, the loss of estrogen receptor A (ERA) is associated with increased cell invasiveness. We have examined the influence of exogenous truncated recombinant TF (rTF) on ERA expression and cell invasiveness and investigated the mechanism of rTF signaling. The influence of rTF on ERA expression in MCF-7 and T47D cell lines was investigated using reverse transcription-PCR and ELISA. Cell invasion was measured using Boyden chamber-based invasion assays. Additionally, the interaction of fluorescein-labeled rTF with the surface of MCF-7 cells and particularly with B 1 -integrin was examined. Treatment of cells with rTF resulted in the downregulation of ERA mRNA and protein over 24 h, which required B 1 -integrin and involved the mitogen-activated protein kinase pathway but did not require PAR2 activation. The addition of rTF reduced estradiol-mediated cell proliferation as well as increased cell invasiveness requiring both PAR2 and B 1 -integrin activation. Fluorescein-labeled rTF was shown to bind to the surface of MCF-7 cells within 5 min and peaked at 15 min. The bound rTF colocalized with cellular B 1 -integrin and was disrupted in the presence of excess unlabeled rTF and an anti-B 1 polyclonal antibody. Finally, affinity purification of B 1 -integrin using rTF-conjugated agarose showed a requirement for the presence of divalent cations but not factor VIIa. The results indicate that rTF is capable of down-regulating ERA expression in breast cancer cells, resulting in decreases in estrogen-mediated cell proliferation and increased invasiveness. Furthermore, the mechanisms by which rTF induces these changes involve both PAR2 and B 1 -integrin.

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“…Furthermore, there are very few reported modalities to address the potential benefits of simultaneous down-regulation of ER and PR, or the predictive value of the pharmacologic modulation of PR in addition to ER. Although PR levels are induced by ER, PR may become hormone independent upon transformation to a more aggressive phenotype (17)(18)(19). The role of PR as a target for endocrine therapy is still under debate and very little is known about the interaction between HDAC enzymes and PR.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylase 2 Silences Progesterone Receptor–Mediated Signaling

et al. 2008

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Several histone deacetylases (HDAC) are involved in estrogen receptor (ER)-mediated gene transactivation, and HDAC inhibitors have been reported to restore sensitivity to antihormonal therapy. The modulation of ER is the most promising approach to ER-expressing breast cancers. Recent studies further suggest a critical role of the progesterone receptor (PR) on ER signaling. Although HDAC inhibitors modulate ER, little is known about their effects on PR. We evaluated the roles of specific HDAC isoenzymes and their inhibition on both ER and PR signaling and their importance in response to endocrine therapy. The roles of individual HDAC isoenzymes on ER and PR expression and their functions were evaluated by depletion of select HDAC enzymes using siRNA or pharmacologic inhibition. Cotreatment of breast cancer cell lines with HDAC inhibitors and the antiestrogen, tamoxifen, resulted in synergistic antitumor activity with simultaneous depletion of both ER and PR. Selective inhibition of HDAC2, but not HDAC1 or HDAC6, was sufficient to potentiate tamoxifen-induced apoptosis in ER/PR-positive cells. Depletion of HDAC1 and HDAC6 was associated with down-regulation of ER but not PR. Only the selective depletion of HDAC2 siRNA down-regulated both ER and PR expression, and was sufficient to potentiate tamoxifen. Selective depletion of HDAC2 resulted in simultaneous depletion of ER and PR, and potentiated the effects of antihormonal therapy in ER-positive cells. A more effective pharmacologic inhibition of HDAC2 and evaluation of HDAC2 and PR as therapeutic targets or as predictive markers in hormonal therapy may be considered when combining HDAC inhibitors and hormonal therapy. [Cancer Res 2008;68(5):1513-9]

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Progesterone Increases Tissue Factor Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer Cell Line ZR-75-1

Cited by 52 publications

References 41 publications

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Influence of Exogenous Tissue Factor on Estrogen Receptorα Expression in Breast Cancer Cells: Involvement of β1-Integrin, PAR2, and Mitogen-Activated Protein Kinase Activation

Selective Inhibition of Histone Deacetylase 2 Silences Progesterone Receptor–Mediated Signaling

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