RESUMO
Microbiomes often benefit plants, conferring resistance to pathogens, improving stress tolerance, or promoting plant growth. As potential plant mutualists, however, microbiomes are not a single organism but a community of species with complex interactions among microbial taxa and between microbes and their shared host. The nature of ecological interactions among microbes in the microbiome can have important consequences for the net effects of microbiomes on hosts. Here, we compared the effects of individual microbial strains and 10-strain synthetic communities on microbial productivity and host growth using the common duckweed Lemna minor and a synthetic, simplified version of its native microbiome. Except for Pseudomonas protegens, which was a mutualist when tested alone, all of the single strains we tested were commensals on hosts, benefiting from plant presence but not increasing host growth relative to uninoculated controls. However, 10-strain synthetic microbial communities increased both microbial productivity and duckweed growth more than the average single-strain inoculation and uninoculated controls, meaning that host-microbiome mutualisms can emerge from community interactions among microbes on hosts. The effects of community inoculation were sub-additive, suggesting at least some competition among microbes in the duckweed microbiome. We also investigated the relationship between L. minor fitness and that of its microbes, providing some of the first empirical estimates of broad fitness alignment between plants and members of their microbiomes; hosts grew faster with more productive microbes or microbiomes. IMPORTANCE: There is currently substantial interest in engineering synthetic microbiomes for health or agricultural applications. One key question is how multi-strain microbial communities differ from single microbial strains in their productivity and effects on hosts. We tested 20 single bacterial strains and 2 distinct 10-strain synthetic communities on plant hosts and found that 10-strain communities led to faster host growth and greater microbial productivity than the average, but not the best, single strain. Furthermore, the microbial strains or communities that achieved the greatest cell densities were also the most beneficial to their hosts, showing that both specific single strains and multi-strain synthetic communities can engage in high-quality mutualisms with their hosts. Our results suggest that ~5% of single strains, as well as multi-strain synthetic communities comprised largely of commensal microbes, can benefit hosts and result in effective host-microbe mutualisms.
Assuntos
Araceae , Microbiota , Simbiose , Araceae/microbiologia , Araceae/crescimento & desenvolvimento , Pseudomonas/genética , Pseudomonas/fisiologia , Interações entre Hospedeiro e Microrganismos , Interações MicrobianasRESUMO
An organism's phenotypes and fitness often depend on the interactive effects of its genome (Ghâ¢oâ¢sâ¢t), microbiome (Gmâ¢iâ¢câ¢râ¢oâ¢bâ¢e), and environment (E). These G × G, G × E, and G × G × E effects fundamentally shape host-microbiome (co)evolution and may be widespread, but are rarely compared within a single experiment. We collected and cultured Lâ¢eâ¢mâ¢nâ¢amâ¢iâ¢nâ¢oâ¢r (duckweed) and its associated microbiome from 10 sites across an urban-to-rural ecotone. We factorially manipulated host genotype and microbiome in two environments (low and high zinc, an urban aquatic stressor) in an experiment with 200 treatments: 10 host genotypes × 10 microbiomes × 2 environments. Host genotype explained the most variation in L.mâ¢iâ¢nâ¢oâ¢r fitness and traits, while microbiome effects often depended on host genotype (G × G). Microbiome composition predicted G × G effects: when compared in more similar microbiomes, duckweed genotypes had more similar effects on traits. Further, host fitness increased and microbes grew faster when applied microbiomes more closely matched the host's field microbiome, suggesting some local adaptation between hosts and microbiota. Finally, selection on and heritability of host traits shifted across microbiomes and zinc exposure. Thus, we found that microbiomes impact host fitness, trait expression, and heritability, with implications for host-microbiome evolution and microbiome breeding.
Assuntos
Genoma , Microbiota , Genótipo , Fenótipo , Microbiota/genética , ZincoRESUMO
Studying the complex web of interactions in biological communities requires large multifactorial experiments with sufficient statistical power. Automation tools reduce the time and labor associated with setup, data collection, and analysis in experiments that untangle these webs. We developed tools for high-throughput experimentation (HTE) in duckweeds, small aquatic plants that are amenable to autonomous experimental preparation and image-based phenotyping. We showcase the abilities of our HTE system in a study with 6,000 experimental units grown across 2,000 treatments. These automated tools facilitated the collection and analysis of time-resolved growth data, which revealed finer dynamics of plant-microbe interactions across environmental gradients. Altogether, our HTE system can run experiments with up to 11,520 experimental units and can be adapted for other small organisms.
Assuntos
Diagnóstico por Imagem , PlantasRESUMO
Chemical identification of microplastics is time-consuming, especially when particles are numerous. To save resources, a subsample of particles is often selected for chemical identification. Because no standard subsampling protocols currently exist, methods vary widely and often lack evidence of representativeness, limiting conclusions and cross-study comparability. In this study, we determine best practices for subsampling >100 µm microparticles for chemical identification based on two research objectives: 1) quantifying the proportion of plastic, anthropogenic and natural particles and 2) quantifying the diversity of material types. Using published datasets where all microparticles counted were chemically identified, we tested subsampling methods where particles are selected either from individual samples, or from a group of samples treated collectively. We determine that overall, particle selection at random provides a representative subsample with the lowest effort. Subsampling methods must also be informed by your research objective. Fewer particles are required to accurately represent the proportion of plastic, anthropogenic and natural particles present, compared to representing the diversity of material types. To accurately represent particle diversity, researchers must understand particle diversity within the environmental matrix in question which informs necessary sampling volume. Overall, harmonized, and representative subsampling practices will allow improved comparability among studies, transparent data reporting, and more robust conclusions.
Assuntos
Microplásticos , Poluentes Químicos da Água , Plásticos , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodosRESUMO
Urbanization impacts land, air, and water, creating environmental gradients between cities and rural areas. Urban stormwater delivers myriad co-occurring, understudied, and mostly unregulated contaminants to aquatic ecosystems, causing a pollution gradient. Recipient ecosystems host interacting species that can affect each others' growth and responses to these contaminants. For example, plants and their microbiomes often reciprocally increase growth and contaminant tolerance. Here, we identified ecological variables affecting contaminant fate across an urban-rural gradient using 50 sources of the aquatic plant Lemna minor (duckweed) and associated microbes, and two co-occurring winter contaminants of temperate cities, benzotriazole and salt. We conducted experiments totalling >2,500 independent host-microbe-contaminant microcosms. Benzotriazole and salt negatively affected duckweed growth, but not microbial growth, and duckweeds maintained faster growth with their local, rather than disrupted, microbiota. Benzotriazole transformation products of plant, microbial, and phototransformation pathways were linked to duckweed and microbial growth, and were affected by salt co-contamination, microbiome disruption, and source sites of duckweeds and microbes. Duckweeds from urban sites grew faster and enhanced phytotransformation, but supported less total transformation of benzotriazole. Increasing microbial community diversity correlated with greater removal of benzotriazole, but taxonomic groups may explain shifts across transformation pathways: the genus Aeromonas was linked to increasing phototransformation. Because benzotriazole toxicity could depend on amount and type of in situ transformation, this variation across duckweeds and microbes could be harnessed for better management of urban stormwater. Broadly, our results demonstrate that plant-microbiome interactions harbour manipulable variation for bioremediation applications.
Assuntos
Araceae , Microbiota , Bactérias , Biodegradação Ambiental , Água Doce , Urbanização , ÁguaRESUMO
We now know that nanoplastics can harm aquatic organisms, but understanding ecological risk starts with understanding fate. We coupled population balance and fugacity models to predict the conditions under which nanoplastics remain as single particles, aggregate, or sediment and to predict their capacity to concentrate organic pollutants. We carried out simulations across a broad range of nanoplastic concentrations, particle sizes, and particle-particle interactions under a range of salinity and organic matter conditions. The model predicts that across plastic materials and environmental conditions, nanoplastics will either remain mostly dispersed or settle as aggregates with natural colloids. Nanoplastics of different size classes respond dissimilarly to concentration, ionic strength, and organic matter content, indicating that the sizes of nanoplastics to which organisms are exposed likely shift across ecological zones. We implemented a fugacity model of the Great Lakes to assess the organic pollution payload carried by nanoplastics, generating the expectation that nanoplastics would carry nine times more pollutants than microsized plastics and a threshold concentration of 10 µg/L at which they impact pollutant distribution. Our simulations across a broad range of factors inform future experimentation by highlighting the relative importance of size, concentration, material properties, and interactions in driving nanoplastic fate in aquatic environments.
Assuntos
Microplásticos , Poluentes Químicos da Água , Organismos Aquáticos , Tamanho da Partícula , Plásticos , Salinidade , Poluentes Químicos da Água/análiseRESUMO
In the common sunflower, patterns of UV-absorbing pigments are controlled by a newly identified regulatory region and may be under the influence of environmental factors.
Assuntos
Helianthus , Cor , Flores , PigmentaçãoRESUMO
Anthropogenic stressors can affect individual species and alter species interactions. Moreover, species interactions or the presence of multiple stressors can modify the stressor effects, yet most work focuses on single stressors and single species. Plant-microbe interactions are a class of species interactions on which ecosystems and agricultural systems depend, yet may be affected by multiple global change stressors. Here, we use duckweed and microbes from its microbiome to model responses of interacting plants and microbes to multiple stressors: climate change and tire wear particles. Climate change is occurring globally, and microplastic tire wear particles from roads now reach many ecosystems. We paired perpendicular gradients of temperature and carbon dioxide (CO2) treatments with factorial manipulation of leachate from tire wear particles and duckweed microbiomes. We found that tire leachate and warmer temperatures enhanced duckweed and microbial growth, but caused effects of microbes on duckweed to become negative. However, induced negative effects of microbes were less than additive with warming and leachate. Without tire leachate, we observed that higher CO2 and temperature induced positive correlations between duckweed and microbial growth, which can strengthen mutualisms. In contrast, with tire leachate, growth correlations were never positive, and shifted negative at lower CO2, again suggesting leachate disrupts this plant-microbiome mutualism. In summary, our results demonstrate that multiple interacting stressors can affect multiple interacting species, and that leachate from tire wear particles could potentially disrupt plant-microbe mutualisms.
Assuntos
Microbiota , Microplásticos , Efeitos Antropogênicos , Dióxido de Carbono , Mudança Climática , Plásticos , Simbiose , TemperaturaRESUMO
The ecological impact of tire wear particles in aquatic ecosystems is a growing environmental concern. We combined toxicity testing, using fathead minnow (Pimephales promelas) embryos, with nontarget high-resolution liquid chromatography Orbitrap mass spectrometry to characterize the toxicity and chemical mixture of organic chemicals associated with tire particle leachates. We assessed: 1) exposure to tire particle leachates after leaching for 1-, 3-, and 10-d; and 2) the effect of the presence and absence of small tire particulates in the leachates. We observed a decrease in embryonic heart rates, hatching success, and lengths, as well as an increase in the number of embryos with severe deformities and diminished eye and body pigmentation, after exposure to the leachates. Overall, there was a pattern whereby we observed more toxicity in the 10-d leachates, and greater toxicity in unfiltered leachates. Redundancy analysis showed that several benzothiazoles and aryl-amines were correlated with the toxic effects observed in the embryos. These included benzothiazole, 2-aminobenzothiazole, 2-mercaptobenzothiazole, N,N'-diphenylguanidine, and N,N'-diphenylurea. However, many other chemicals characterized as unknowns are likely to also play a key role in the adverse effects observed. Our study provides insight into the types of chemicals likely to be important toxicological drivers in tire leachates, and improves our understanding of the ecotoxicological impacts of tire wear particles. Environ Toxicol Chem 2022;41:1144-1153. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Assuntos
Cyprinidae , Poluentes Químicos da Água , Animais , Ecossistema , Ecotoxicologia , Testes de Toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
Plant development and the timing of developmental events (phenology) are tightly coupled with plant fitness. A variety of internal and external factors determine the timing and fitness consequences of these life-history transitions. Microbes interact with plants throughout their life history and impact host phenology. This review summarizes current mechanistic and theoretical knowledge surrounding microbe-driven changes in plant phenology. Overall, there are examples of microbes impacting every phenological transition. While most studies have focused on flowering time, microbial effects remain important for host survival and fitness across all phenological phases. Microbe-mediated changes in nutrient acquisition and phytohormone signaling can release plants from stressful conditions and alter plant stress responses inducing shifts in developmental events. The frequency and direction of phenological effects appear to be partly determined by the lifestyle and the underlying nature of a plant-microbe interaction (i.e., mutualistic or pathogenic), in addition to the taxonomic group of the microbe (fungi vs. bacteria). Finally, we highlight biases, gaps in knowledge, and future directions. This biotic source of plasticity for plant adaptation will serve an important role in sustaining plant biodiversity and managing agriculture under the pressures of climate change.
Assuntos
Mudança Climática , Plantas , Biodiversidade , Desenvolvimento Vegetal , Estações do Ano , SimbioseRESUMO
Evolutionary biologists typically envision a trait's genetic basis and fitness effects occurring within a single species. However, traits can be determined by and have fitness consequences for interacting species, thus evolving in multiple genomes. This is especially likely in mutualisms, where species exchange fitness benefits and can associate over long periods of time. Partners may experience evolutionary conflict over the value of a multi-genomic trait, but such conflicts may be ameliorated by mutualism's positive fitness feedbacks. Here, we develop a simulation model of a host-microbe mutualism to explore the evolution of a multi-genomic trait. Coevolutionary outcomes depend on whether hosts and microbes have similar or different optimal trait values, strengths of selection and fitness feedbacks. We show that genome-wide association studies can map joint traits to loci in multiple genomes and describe how fitness conflict and fitness feedback generate different multi-genomic architectures with distinct signals around segregating loci. Partner fitnesses can be positively correlated even when partners are in conflict over the value of a multi-genomic trait, and conflict can generate strong mutualistic dependency. While fitness alignment facilitates rapid adaptation to a new optimum, conflict maintains genetic variation and evolvability, with implications for applied microbiome science.
Assuntos
Microbiota , Simbiose , Evolução Biológica , Estudo de Associação Genômica Ampla , FenótipoRESUMO
Advances in microbiome science require a better understanding of how beneficial microbes adapt to hosts. We tested whether hosts select for more-cooperative microbial strains with a year-long evolution experiment and a cross-inoculation experiment designed to explore how nitrogen-fixing bacteria (rhizobia) adapt to legumes. We paired the bacterium Ensifer meliloti with one of five Medicago truncatula genotypes that vary in how strongly they "choose" bacterial symbionts. Independent of host choice, E. meliloti rapidly adapted to its local host genotype, and derived microbes were more beneficial when they shared evolutionary history with their host. This local adaptation was mostly limited to the symbiosis plasmids, with mutations in putative signaling genes. Thus, cooperation depends on the match between partner genotypes and increases as bacteria adapt to their local host.
Assuntos
Adaptação Biológica , Interações entre Hospedeiro e Microrganismos/genética , Medicago truncatula/genética , Medicago truncatula/microbiologia , Microbiota/fisiologia , Sinorhizobium meliloti/fisiologia , SimbioseRESUMO
The picture emerging from the rapidly growing literature on host-associated microbiota is that host traits and fitness often depend on interactive effects of host genotype, microbiota, and abiotic environment. However, testing interactive effects typically requires large, multi-factorial experiments and thus remains challenging in many systems. Furthermore, most studies of plant microbiomes focus on terrestrial hosts and microbes. Aquatic habitats may confer unique properties to microbiomes. We grew different populations of duckweed (Lemna minor), a floating aquatic plant, in three microbial treatments (adding no, "home", or "away" microbes) at two levels of zinc, a common water contaminant in urban areas, and measured both plant and microbial performance. Thus, we simultaneously manipulated plant source population, microbial community, and abiotic environment. We found strong effects of plant source, microbial treatment, and zinc on duckweed and microbial growth, with significant variation among duckweed genotypes and microbial communities. However, we found little evidence of interactive effects: zinc did not alter effects of host genotype or microbial community, and host genotype did not alter effects of microbial communities. Despite strong positive correlations between duckweed and microbe growth, zinc consistently decreased plant growth, but increased microbial growth. Furthermore, as in recent studies of terrestrial plants, microbial interactions altered a duckweed phenotype (frond aggregation). Our results suggest that duckweed source population, associated microbiome, and contaminant environment should all be considered for duckweed applications, such as phytoremediation. Lastly, we propose that duckweed microbes offer a robust experimental system for study of host-microbiota interactions under a range of environmental stresses.
Assuntos
Araceae/microbiologia , Bactérias/crescimento & desenvolvimento , Microbiota/fisiologia , Simbiose , Poluentes Químicos da Água/efeitos adversos , Zinco/efeitos adversos , Araceae/efeitos dos fármacos , Araceae/genética , Araceae/crescimento & desenvolvimento , Aptidão Genética , Genótipo , Interações entre Hospedeiro e MicrorganismosRESUMO
While the combined presence of global climate change and nanosized plastic particle (i.e., nanoplastic) pollution is clear, the potential for interactions between climate-change-shifting environmental parameters and nanoplastics is largely unknown. Here, we aim to understand how nanoplastics will affect species in concert with climate change in freshwater ecosystems. We utilized a high-throughput full-factorial experimental system and the model photosynthetic microorganism Scenedesmus obliquus to capture the complexity of interacting environmental stressors, including CO2, temperature, light, and nanoplastics. Under a massive number of conditions (2000+), we consistently found concentration-dependent inhibition of algal growth in the presence of polystyrene nanoparticles, highlighting a threat to primary productivity in aquatic ecosystems. Our high-treatment experiment also identified crucial interactions between nanoplastics and climate change. We found that relatively low temperature and ambient CO2 exacerbated damage induced by nanoplastics, while elevated CO2 and warmer temperatures reflecting climate change scenarios somewhat attenuated nanoplastic toxicity. Further, we revealed that nanoplastics may modulate light responses, implying that risks of nanoplastic pollution may also depend on local irradiation conditions. Our study highlights the coupled impacts of nanoplastics and climate change, as well as the value of full-factorial screening in predicting biological responses to multifaceted global change.
Assuntos
Mudança Climática , Ecossistema , Água Doce , Plásticos , PoliestirenosRESUMO
PREMISE: Outcomes of species interactions, especially mutualisms, are notoriously dependent on environmental context, and environments are changing rapidly. Studies have investigated how mutualisms respond to or ameliorate anthropogenic environmental changes, but most have focused on nutrient pollution or climate change and tested stressors one at a time. Relatively little is known about how mutualisms may be altered by or buffer the effects of multiple chemical contaminants, which differ fundamentally from nutrient or climate stressors and are especially widespread in aquatic habitats. METHODS: We investigated the impacts of two contaminants on interactions between the duckweed Lemna minor and its microbiome. Sodium chloride (salt) and benzotriazole (a corrosion inhibitor) often co-occur in runoff to water bodies where duckweeds reside. We tested three L. minor genotypes with and without the culturable portion of their microbiome across field-realistic gradients of salt (3 levels) and benzotriazole (4 levels) in a fully factorial experiment (24 treatments, tested on each genotype) and measured plant and microbial growth. RESULTS: Stressors had conditional effects. Salt decreased both plant and microbial growth and decreased plant survival more as benzotriazole concentrations increased. In contrast, benzotriazole did not affect microbial abundance and even benefited plants when salt and microbes were absent, perhaps due to biotransformation into growth-promoting compounds. Microbes did not ameliorate duckweed stressors; microbial inoculation increased plant growth, but not at high salt concentrations. CONCLUSIONS: Our results suggest that multiple stressors matter when predicting responses of mutualisms to global change and that beneficial microbes may not always buffer hosts against stress.
Assuntos
Araceae , Microbiota , Desenvolvimento Vegetal , Cloreto de SódioRESUMO
Climate is a powerful force shaping adaptation within species, yet adaptation to climate occurs against a biotic background: species interactions can filter fitness consequences of genetic variation by altering phenotypic expression of genotypes. We investigated this process using populations of teosinte, a wild annual grass related to maize (Zea mays ssp. mexicana), sampling plants from 10 sites along an elevational gradient as well as rhizosphere biota from three of those sites. We grew half-sibling teosinte families in each biota to test whether trait divergence among teosinte populations reflects adaptation or drift, and whether rhizosphere biota affect expression of diverged traits. We further assayed the influence of rhizosphere biota on contemporary additive genetic variation. We found that adaptation across environment shaped divergence of some traits, particularly flowering time and root biomass. We also observed that different rhizosphere biota shifted expressed values of these traits within teosinte populations and families and altered within-population genetic variance and covariance. In sum, our results imply that changes in trait expression and covariance elicited by rhizosphere communities could have played a historical role in teosinte adaptation to environments and that they are likely to play a role in the response to future selection.
Assuntos
Aclimatação , Biota , Variação Genética , Zea mays/genética , Evolução Molecular , Flores/genética , Fenótipo , Característica Quantitativa Herdável , Rizosfera , Zea mays/fisiologiaRESUMO
Expression of plant phenotypes can depend on both plant genomes and interactions between plants and the microbes living in, on and near their roots. We understand a growing number of the mechanistic links between plant genotypes and phenotypes, such as defence against herbivory (see brief review in Hubbard et al., ), yet the links between root microbiomes and the comprehensive swathe of plant phenotypes they affect (Friesen et al., ) remain less clear. In this issue of Molecular Ecology, Hubbard et al. () follow microbe- and plant-driven changes in plant defence against hervibory from molecular underpinnings to ecological consequences, contrasting both the metabolites affected and the magnitude of defensive impact. Naively, we might expect plant genomes to drive more variation in phenotype than the root microbiome, but Hubbard et al. () find the opposite, implying profound consequences for plant trait evolution and ecological interactions.
Assuntos
Herbivoria , Rizosfera , Animais , Insetos , Redes e Vias Metabólicas , Microbiologia do SoloRESUMO
The outcomes of many species interactions are conditional on the environments in which they occur. Often, interactions grade from being more positive under stressful or low-resource conditions to more antagonistic or neutral under benign conditions. Here, we take predictions about two well-supported ecological theories on conditionality-limiting resource models and the stress-gradient hypothesis-and combine them with those from the geographic mosaic theory of coevolution (GMTC) to generate predictions for systematic patterns of adaptation and coadaptation between partners along abiotic gradients. When interactions become more positive in stressful environments, mutations that increase fitness in one partner may also increase fitness in the other; because fitnesses are aligned, selection should favor greater mutualistic adaptation and coadaptation between interacting species in stressful ends of environmental gradients. As a corollary, in benign environments antagonistic coadaptation could result in Red Queen or arms-race dynamics or the reduction of antagonism through character displacement and niche partitioning. Here, we distinguish between generally mutualistic or antagonistic adaptation (i.e., mutations in one partner that have similar effects across multiple populations of the other) and specific adaptations to sympatric partners (local adaptation), which can occur either alone or simultaneously. We then outline the kinds of data required to test these predictions, develop experimental designs and statistical methods, and demonstrate these using simulations based on GMTC models. Our methods can be applied to a range of conditional outcomes and may also be useful in assisted translocation approaches in the face of climate change.
Assuntos
Coevolução Biológica , Simbiose , Adaptação Fisiológica , Evolução Biológica , Simulação por Computador , Ecossistema , Geografia , Modelos Genéticos , MutaçãoRESUMO
BACKGROUND: The inhibition of Breast Cancer 1 (BRCA1) expression sensitizes breast and ovarian cancer cells to platinum chemotherapy. However, therapeutically relevant agents that target BRCA1 expression have not been identified. Our recent report suggested the potential of the histone deacetylase (HDAC) inhibitor, M344, to inhibit BRCA1 expression. In this study, we further evaluated the effect of M344 on BRCA1 mRNA and protein expression, as well as its effect on cisplatin-induced cytotoxicity in various breast (MCF7, T-47D and HCC1937) and ovarian (A2780s, A2780cp and OVCAR-4) cancer cell lines. RESULTS: With the addition of M344, the platinum-sensitive breast and ovarian cancer cell lines that displayed relatively high BRCA1 protein levels demonstrated significant potentiation of cisplatin cytotoxicity in association with a reduction of BRCA1 protein. The cisplatin-resistant cell lines, T-47D and A2780s, elicited increased cytotoxicity of cisplatin with M344 and down regulation of BRCA1 protein levels. A2780s cells subjected to combination platinum and M344 treatment, demonstrated increased DNA damage as assessed by the presence of phosphorylated H2A.X foci in comparison to either treatment alone. Using Chromatin Immunoprecipitation, A2780s and MCF7 cells exposed to M344 alone and in combination with cisplatin, did not demonstrate enhanced acetylated Histone 4 at the BRCA1 promoter, suggesting an indirect effect on this promoter. CONCLUSIONS: The enhanced sensitivity of HDAC inhibition to platinum may be mediated through a BRCA1-dependent mechanism in breast and ovarian cancer cells. The findings of this study may be important in the future design of clinical trials involving HDAC inhibitors using BRCA1 as a tumour biomarker.
RESUMO
In sporadic epithelial ovarian cancer (EOC), the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients with BRCA1 germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.