CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival.

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

High content drug screening for Fanconi anemia therapeutics.

BACKGROUND: Fanconi anemia is a rare disease clinically characterized by malformations, bone marrow failure and an increased risk of solid tumors and hematologic malignancies. The only therapies available are hematopoietic stem cell transplantation for bone marrow failure or leukemia, and surgical resection for solid tumors. Therefore, there is still an urgent need for new therapeutic options. With this aim, we developed a novel high-content cell-based screening assay to identify drugs with therapeutic potential in FA. RESULTS: A TALEN-mediated FANCA-deficient U2OS cell line was stably transfected with YFP-FANCD2 fusion protein. These cells were unable to form fluorescent foci or to monoubiquitinate endogenous or exogenous FANCD2 upon DNA damage and were more sensitive to mitomycin C when compared to the parental wild type counterpart. FANCA correction by retroviral infection restored the cell line's ability to form FANCD2 foci and ubiquitinate FANCD2. The feasibility of this cell-based system was interrogated in a high content screening of 3802 compounds, including a Prestwick library of 1200 FDA-approved drugs. The potential hits identified were then individually tested for their ability to rescue FANCD2 foci and monoubiquitination, and chromosomal stability in the absence of FANCA. CONCLUSIONS: While, unfortunately, none of the compounds tested were able to restore cellular FANCA-deficiency, our study shows the potential capacity to screen large compound libraries in the context of Fanconi anemia therapeutics in an optimized and cost-effective platform.

Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia-Related Head and Neck Cancer.

PURPOSE: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia. EXPERIMENTAL DESIGN: We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety. RESULTS: Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters. CONCLUSIONS: Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.

Transexualidad y reproducción: situación actual desde el punto de vista clínico y legal / Transsexualism and reproduction: Clinical and legal situation

Se diagnostican como transexuales las personas que se identifican con el sexo opuesto y rechazan el género propio. Existen distintas hipótesis que intentan explicar el origen de la transexualidad, siendo las más aceptadas las teorías con bases biológicas. La prevalencia estimada es variable en función de la zona geográfica, siendo más frecuentes los transexuales femeninos que los masculinos. Las técnicas de reproducción asistida facilitan las opciones reproductivas de este colectivo que acude, cada vez más, a los centros clínicos especializados para tratar de formar una familia defendiendo el derecho a la reproducción de todo ser humano. Los transexuales pueden verse favorecidos especialmente por las técnicas de preservación de la fertilidad, pudiendo criopreservar sus gametos antes de la reasignación de sexo como estrategia preventiva en vistas a un posible deseo de reproducción futura. La falta de recomendaciones o guías consensuadas sobre la aplicabilidad de las técnicas de reproducción asistida en individuos transexuales y el vacío normativo existente dificultan su acceso a estas técnicas. Esta revisión recoge las posibles opciones reproductivas de los transexuales desde un punto de vista clínico y analiza la situación actual en el marco de la legislación española vigente (AU)

People who identify themselves with the opposite sex and reject their own gender are diagnosed as transsexuals. Different hypotheses have tried to explain the origin of transsexualism, biological theories being the most accepted. The estimated prevalence is variable, this depending on the geographic area. Female are more frequent than male transsexuals. Assisted reproduction techniques facilitate the reproductive options of this group who increasingly come to specialized clinical centers to try to form a family, defending the reproductive rights of every human being. Transsexuals could be especially favored by fertility preservation techniques, being able to cryopreserve their gametes before sex reassignment as a preventive strategy in view of a possible desire for future reproduction. Lack of recommendations or agreed on guidelines and absence of regulations about the applicability of assisted reproduction in transsexuals hinders their access to these techniques. This review summarizes the possible reproductive options of transsexuals from a clinical point of view and analyzes the current situation in the framework of Spanish law (AU)