BRCA Mutations-The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers.

Two related tumor suppressor genes, BRCA1 and BRCA2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review, we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanisms of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on the mechanisms of DNA damage repair where these proteins are involved, and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also discuss a hypothesis explaining why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss prospective novel therapeutic approaches for treating BRCAness cancers.

Albumin incorporation into recognising layer of HER2-specific magnetic nanoparticles as a tool for optimal targeting of the acidic tumor microenvironment.

Cancer is unquestionably a global healthcare challenge, spurring the exporation of novel treatment approaches. In recent years, nanomaterials have garnered significant interest with the greatest hopes for targeted nanoformulations due to their cell-specific delivery, improved therapeutic efficacy, and reduced systemic toxicity for the organism. The problem of successful clinical translation of nanoparticles may be related to the fact that most in vitro tests are performed at pH values of normal cells and tissues, ranging from 7.2 to 7.4. The extracellular pH values of tumors are characterized by a shift to a more acidic region in the range of 5.6-7.0 and represent a crucial target for enhancing nanoparticle delivery to cancer cells. Here we show the method of non-active protein incorporation into the surface of HER2-targeted nanoparticles to achieve optimal cellular uptake within the pH range of the tumor microenvironment. The method efficacy was confirmed in vitro and in vivo showing the maximum binding of nanoparticles to cells at a pH value 6.4. Namely, fluorescent magnetic nanoparticles, modified with HER2-recognising affibody ZHER2:342, with proven specificity in terms of HER2 recognition (with 62-fold higher cellular uptake compared to control nanoparticles) were designed for targeting cancer cells at slightly acidic pH values. The stabilizing protein, namely, bovine serum albumin, one of the major blood components with widespread availability and biocompatibility, was used for the decoration of the nanoparticle surface to alter the pH response of the targeting magnetic conjugates. The optimally designed nanoparticles showed a bell-shaped dependency of interaction with cancer cells in the pH range of 5.6-8.0 with maximum cellular uptake at pH value 6.4 close to that of the tumor microenvironment. In vivo experiments revealed that after i.v. administration, BSA-decorated nanoparticles exhibited 2 times higher accumulation in tumors compared to magnetic nanoparticles modified with affibody only. Thus, we demonstrated a valid method for enhancing the specificity of targeted nanoparticle delivery to cancer cells without changing the functional components of nanoparticles.

Polypurine (A)-rich sequences promote cross-kingdom conservation of internal ribosome entry.

The internal ribosome entry sites (IRES), IRES(CP,148)(CR) and IRES(MP,75)(CR), precede the coat protein (CP) and movement protein (MP) genes of crucifer-infecting tobamovirus (crTMV), respectively. In the present work, we analyzed the activity of these elements in transgenic plants and other organisms. Comparison of the relative activities of the crTMV IRES elements and the IRES from an animal virus--encephalomyocarditis virus--in plant, yeast, and HeLa cells identified the 148-nt IRES(CP,148)(CR) as the strongest element that also displayed IRES activity across all kingdoms. Deletion analysis suggested that the polypurine (A)-rich sequences (PARSs) contained in IRES(CP,148)(CR) are responsible for these features. On the basis of those findings, we designed artificial PARS-containing elements and showed that they, too, promote internal translation from dicistronic transcripts in vitro, in tobacco protoplasts and in HeLa cells. The maximum IRES activity was obtained from multiple copies of either (A)(4)G(A)(2)(G)(2) or G(A)(2-5) as contained in IRES(CP,148)(CR). Remarkably, even homopolymeric poly(A) was moderately active, whereas a poly(G) homopolymer was not active. Furthermore, a database search for existing PARS sequences in 5'-untranslated regions (5'UTR) of genes in tobacco genome allowed the easy identification of a number of IRES candidates, in particular in the 5'UTR of the gene encoding Nicotiana tabacum heat-shock factor 1 (NtHSF1). Consistent with our prediction, the 5'UTR of NtHSF1 turned out to be an IRES element active in vitro, in plant protoplasts and HeLa cells. We predict that PARS elements, when found in other mRNAs, will show a similar activity.