FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer

Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan−Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan−Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk

The estrogen receptor alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships

Background: Insulin receptor substrate 1 (IRS-1) is a signaling molecule that exerts a key role in mediating cross talk between estrogen receptor a (ERa) and insulin-like growth factor 1 (IGF-1) in breast cancer cells. Previously, we demonstrated that a fraction of IRS-1 binds ERa, translocates to the nucleus, and modulates ERa-dependent transcription at estrogen response elements (ERE). Here, we studied structure–function relationships of the ERa:IRS-1 complex under IGF-1 and/or estradiol (E2) stimulation. Materials and methods: ERa and IRS-1 deletion mutants were used to analyze structural and functional ERa/IRS-1 interactions. IRS-1 binding to ERE and IRS-1 role in ERa-dependent ERE transcription was examined by chromatin immunoprecipitation and gene reporter analysis, respectively. The requirement for IRS-1 in ERa function was tested with RNAi technology. Results: Nuclear translocation of IRS-1 was induced by E2, IGF-1, and a combination of both stimuli. ERa/IRS-1 binding was direct and involved the activation function-1 (AF-1)/DNA binding domain (DBD) region of ERa and two discrete regions of IRS-1 (the N-terminal pleckstrin homology domain and a region within the C-terminus). IRS-1 knock down abrogated IGF-1-dependent transcriptional activity of unliganded ERa, but induced the activity of liganded ERa. Conclusions: ERa/IRS-1 interactions are direct and involve the ERa AF-1/DBD domain and IRS-1 domains mapping within N- and C-terminus. IRS-1 may act as a repressor of liganded ERa and coactivator of unliganded ERa

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines

LIMES ET CON-FINIS_abstract

In our research about decoding complex events through the process of graphic abstraction, we investigated a possible visual or mental representation of boundaries. Boundaries are typically built on a large scale and cannot be reduced to a geometric figure. These two properties lead to the following consequence: boundaries are perceived as something immaterial. We all know the role of imagination as a means to be conscious of something and to make it exist. So we tried to create an overall and concise representation of boundaries. To achieve this goal we conducted an analytic study on relevant defensive and military walls, from the ancient Roman Empire to post World War II. We selected 23 case study, classified by the same criteria. At the end, we found out that two categories are prevalent: continuous boundaries and discontinuous boundaries. Both of them are organized into four different typologies. We translated them into graphic symbols which constitute the minimum unit useful to draw a conceptual map. So we condensed a lot of information in a short space and, above all, made visible the invisible

FROM ORNAMENT TO THE CITY. The teaching of Eugène Grasset within the urban design of Le Corbusier. DALL'ORNAMENTO ALLA CITTà . L'insegnamento di Eugène Grasset nel disegno urbano di Le Corbusier

Le Corbusier presents for the first time the Plan de la Ville de 3 millions d’habitants in 1922 at the Salon d’Automne. At that time the Swiss architect had already completed an important part of his artistic training. His training started at the École d’Art municipal in his native town La Chaux–de–Fonds, and continued in his two important training trips in Northern Italy, Vienna and Paris, between 1907–1909; and in Germany and the East between 1910–1911. The young Jeanneret, during these four years of intense research, starts, slowly and painfully, a profound revision of the teachings received from the master Charles L’Eplattenier on the value of ornament. Le Corbusier becomes increasingly critical and projected towards the search for the architecture of tomorrow, coming to repudiate decorative art in 1925 through the homonymous book in which he explains his reasons in detail. Starting from these two elements, in this paper we aim to understand how the lessons learned by the young Le Corbusier about ornament and geometry, are also to be found in his later work and specifically in the conception of this urban design. The Plan de la Ville de 3 millions d’habitants seems to be build on a warp that geometrically controls the plot and defines the urban layout. Similarly, the exercises reported in Méthode de composition ornementale by Eugène Grasset, a book on which Jenneret himself read extensively, reveal the geometric–compositional method applied to obtain new decorative drawings. By decoding the method applied by Grasset for the design of two–dimensional ornaments, we intend to reveal the geometric matrices and the stratifications of urban patterns adopted by Le Corbusier for the layout of the Plan de la Ville de 3 millions d’habitants

JHON HEJDUK AND THE DESIGN METHOD IN HIS WORK. FROM NINE SQUARE GRID PROBLEM TO TEXAS HOUSES

For John Hejduk, the single-family house is an area in which to develop a new representative code. In our research we want to highlight the ordering role that the scheme played in the figurative processes he used. Starting from the series of images of the Texas Houses a sequence of figurative actions has been identified that, using basic principles and elementary geometries, could reconstruct the formal genesis of the planimetric plants. The resulting taxonomy allows the comparison of the generative processes of the figures and the identification of spatial categories

ROLE OF ANDROGEN RECEPTOR IN BREAST CANCER-ASSOCIATED FIBROBLASTS: MAY ANDROGEN SHAPE BREAST TUMOR MICROENVIRONMENT?

Interaction between breast tumor epithelial and stromal cells is central for tumor growth and progression.Indeed, while providing a scaffold for the breast, the stroma also regulates epithelial cell function throughphysical and hormonal paracrine exchanges, providing a favorable environment for proliferation andmetastasis. There is extensive knowledge of androgen receptor (AR) signaling in breast epithelial cancercells, but less regarding AR-mediated action in breast tumor stroma. In the present report, we provideevidence of AR expression in breast cancer-associated fibroblasts (CAFs) isolated from breast cancerpatients. We also examined the effect of CAFs exposure to androgens on: 1) secretory phenotype and 2) themigratory behavior of the estrogen-responsive breast cancer MCF-7, T47D and ZR-75 cells