RESUMEN
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC. METHODS: Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition. RESULTS: This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins. CONCLUSIONS: This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Quinasa I-kappa B/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Subunidad p52 de NF-kappa B/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Femenino , Humanos , Quinasa I-kappa B/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Subunidad p52 de NF-kappa B/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
In a process similar to exon splicing, ciliates use DNA splicing to produce a new somatic macronuclear genome from their germline micronuclear genome after sexual reproduction. This extra layer of DNA rearrangement permits novel mechanisms to create genetic complexity during both evolution and development. Here we describe a chimeric macronuclear chromosome in Oxytricha trifallax constructed from two smaller macronuclear chromosomes. To determine how the chimera was generated, we cloned and sequenced the corresponding germline loci. The chimera derives from a novel locus in the micronucleus that arose by partial duplication of the loci for the two smaller chromosomes. This suggests that an exon shuffling-like process, which we call MDS shuffling, enables ciliates to generate novel genetic material and gene products using different combinations of genomic DNA segments.
Asunto(s)
Quimera/genética , Duplicación Cromosómica , Oxytricha/genética , Alelos , Secuencia de Bases , Variaciones en el Número de Copia de ADN , Genes Protozoarios , Genoma de Protozoos , Micronúcleo Germinal/genética , Datos de Secuencia Molecular , Cebollas , Recombinación GenéticaRESUMEN
We present a rare case of metastatic pancreatic adenocarcinoma diagnosed antepartum. A high index of suspicion must be maintained to diagnose pancreatic cancer during pregnancy. We recommend a thorough history and physical and aggressive pursuit of sensitive imaging in patients with persistent symptoms. If pancreatic adenocarcinoma is diagnosed, a multidisciplinary approach that focuses on patient goals should be undertaken. The effect of pregnancy on tumor growth rates is unknown.