Esprit Futur : Le Corbusier and José Oubrerie at Saint-Pierre De Firminy, Firminy-Vert, France, 1968–2006

What is the secret mesmerism that death possesses and under the operation of which a modern architect – strident, confident, resolute – becomes rueful, pessimistic, or melancholic?1 Five years before Le Corbusier’s death at sea in 1965, the architect reluctantly agreed to adopt the project for L’Église Saint-Pierre de Firminy in Firminy-Vert (1960–2006), following the death of its original architect, André Sive, from leukemia in 1958.2 Le Corbusier had already developed, in 1956, the plan for an enclave in the new “green” Firminy town, which included his youth and culture center and a stadium and swimming pool; the church and a “boîte à miracles” near the youth center were inserted into the plan in the ’60s. (Le Corbusier was also invited, in 1962, to produce another plan for three Unités d’Habitation outside Firminy-Vert.) The Saint-Pierre church should have been the zenith of the quartet (the largest urban concentration of works by Le Corbusier in Europe, and what the architect Henri Ciriani termed Le Corbusier’s “acropolis”3) but in the early course of the project, Le Corbusier would suffer the diocese’s serial objections to his vision for the church – not unlike the difficulties he experienced with Notre Dame du Haut at Ronchamp (1950–1954) and the resistance to his proposed monastery of Sainte-Marie de la Tourette (1957–1960). In 1964, the bishop of Saint-Étienne requested that Le Corbusier relocate the church to a new site, but Le Corbusier refused and the diocese subsequently withdrew from the project. (With neither the approval, funds, nor the participation of the bishop, by then the cardinal archbishop of Lyon, the first stone of the church was finally laid on the site in 1970.) Le Corbusier’s ambivalence toward the project, even prior to his quarrels with the bishop, reveals...

Remodeling of purinergic receptor-mediated Ca 2+ signaling as a consequence of EGF-induced epithelial-mesenchymal transition in breast cancer cells

Background The microenvironment plays a pivotal role in tumor cell proliferation, survival and migration. Invasive cancer cells face a new set of environmental challenges as they breach the basement membrane and colonize distant organs during the process of metastasis. Phenotypic switching, such as that which occurs during epithelial-mesenchymal transition (EMT), may be associated with a remodeling of cell surface receptors and thus altered responses to signals from the tumor microenvironment. Methodology/Principal Findings We assessed changes in intracellular Ca 2+ in cells loaded with Fluo-4 AM using a fluorometric imaging plate reader (FLIPR TETRA) and observed significant changes in the potency of ATP (EC 50 0.175 μM (-EGF) versus 1.731 μM (+EGF), P<0.05), and the nature of the ATP-induced Ca 2+ transient, corresponding with a 10-fold increase in the mesenchymal marker vimentin (P<0.05). We observed no change in the sensitivity to PAR2-mediated Ca 2+ signaling, indicating that these alterations are not simply a consequence of changes in global Ca 2+ homeostasis. To determine whether changes in ATP-mediated Ca 2+ signaling are preceded by alterations in the transcriptional profile of purinergic receptors, we analyzed the expression of a panel of P2X ionotropic and P2Y metabotropic purinergic receptors using real-time RT-PCR and found significant and specific alterations in the suite of ATP-activated purinergic receptors during EGF-induced EMT in breast cancer cells. Our studies are the first to show that P2X 5 ionotropic receptors are enriched in the mesenchymal phenotype and that silencing of P2X 5 leads to a significant reduction (25%, P<0.05) in EGF-induced vimentin protein expression. Conclusions The acquisition of a new suite of cell surface purinergic receptors is a feature of EGF-mediated EMT in MDA-MB-468 breast cancer cells. Such changes may impart advantageous phenotypic traits and represent a novel mechanism for the targeting of cancer metastasis.

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgenindependent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.