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

Department of Reproductive Medicine and Child Development, University of Pisa, Italy.
Endocrine Related Cancer (Impact Factor: 4.81). 03/2010; 17(2):431-43. DOI: 10.1677/ERC-09-0258
Source: PubMed


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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    • "Notably, it has been shown that non-genomic actions of the ligand-activated PR lead to activation of the RhoA/Rho-associated kinase (ROCK-2) cascade in T47D cells [52], [62]. This signaling pathway, ultimately, directs remodeling of the actin cytoskeleton and formation of membrane ruffles required for cell movement [52]; it, also, leads to rapid activation of the focal adhesion (FA) kinase and increased formation of FA complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion [62]. During preparation of this manuscript a study came out that described the PR-targetome during mammary gland branching morphogenesis [63]. "
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    ABSTRACT: Despite the pleiotropic effects of the progesterone receptor in breast cancer, the molecular mechanisms in play remain largely unknown. To gain a global view of the PR-orchestrated networks, we used next-generation sequencing to determine the progestin-regulated transcriptome in T47D breast cancer cells. We identify a large number of PR target genes involved in critical cellular programs, such as regulation of transcription, apoptosis, cell motion and angiogenesis. Integration of the transcriptomic data with the PR-binding profiling of hormonally treated cells identifies numerous components of the small-GTPases signaling pathways as direct PR targets. Progestin-induced deregulation of the small GTPases may contribute to the PR's role in mammary tumorigenesis. Transcript expression analysis reveals significant expression changes of specific transcript variants in response to the extracellular hormonal stimulus. Using the NET1 gene as an example, we show that the PR can dictate alternative promoter usage leading to the upregulation of an isoform that may play a role in metastatic breast cancer. Future studies should aim to characterize these selectively regulated variants and evaluate their clinical utility in prognosis and targeted therapy of hormonally responsive breast tumors.
    PLoS ONE 06/2014; 9(6):e98404. DOI:10.1371/journal.pone.0098404 · 3.23 Impact Factor
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    • "Magnification is represented by 100 í µí¼‡m scale in all photomicrographs. effect can occur through various mechanisms, including overexpression of proteins such as superoxide dismutase, tissue factor, and protease-activated receptors [33] [34] [35]; the enhancing of matrix metalloproteinases and urokinase-type plasminogen activator activities [36]; the activating of the focal adhesion kinase [37], and the activation of rapid signaling cascades that leads to modifications in the actin cytoskeleton and the cell membrane [38] [39]. In other several cell lines, including glioma cells, it has been found that voltage-gated ion channels play a significant role in initiation "
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    ABSTRACT: Progesterone (P4) promotes cell proliferation in several types of cancer, including brain tumors such as astrocytomas, the most common and aggressive primary intracerebral neoplasm in humans. In this work, we studied the effects of P4 and its intracellular receptor antagonist, RU486, on growth and infiltration of U373 cells derived from a human astrocytoma grade III, implanted in the motor cortex of adult male rats, using two treatment schemes. In the first one, fifteen days after cells implantation, rats were daily subcutaneously treated with vehicle (propylene glycol, 160 μ L), P4 (1 mg), RU486 (5 mg), or P4 + RU486 (1 mg and 5 mg, resp.) for 21 days. In the second one, treatments started 8 weeks after cells implantation and lasted for 14 days. In both schemes we found that P4 significantly increased the tumor area as compared with the rest of the treatments, whereas RU486 blocked P4 effects. All rats treated with P4 showed tumor infiltration, while 28.6% and 42.9% of the animals treated with RU486 and P4 + RU486, respectively, presented it. Our data suggest that P4 promotes growth and migration of human astrocytoma cells implanted in the motor cortex of the rat through the interaction with its intracellular receptor.
    BioMed Research International 05/2014; 2014:393174. DOI:10.1155/2014/393174 · 3.17 Impact Factor
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    • "evale et al . , 2007 ; Castoria et al . , 1999 ; Migliaccio et al . , 2007 ; Proietti et al . , 2005 ; Saitoh et al . , 2005 ; Skildum et al . , 2005 ) . Rapid activation of the PI3K / Akt / Rho / ROCk signaling cascade in breast cancer cells has also been reported to be involved in mediating the effects of P4 on cell motility and focal adhesion ( Fu et al . , 2010 ) . The non - receptor tyrosine kinase c - Src is a central player in mediating rapid activation of signaling cascades by all steroid hormone receptors . Src is proximal in the signaling pathways af - fected , and it can bind steroid receptors either directly or indirectly ( Ballare et al . , 2003 ; Boonyaratanakornkit et al . , 2001 ) "
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    ABSTRACT: This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.
    Molecular and Cellular Endocrinology 12/2011; 357(1-2):4-17. DOI:10.1016/j.mce.2011.10.030 · 4.41 Impact Factor
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