ABSTRACT
BACKGROUND: Little is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. PATIENTS AND METHODS: We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR). RESULTS: Pre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. CONCLUSIONS: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Female , Humans , Ovarian Neoplasms/drug therapy , Platinum/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic useABSTRACT
p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.
Subject(s)
Cytoplasm/genetics , Epithelial-Mesenchymal Transition/genetics , Neoplasm Metastasis/genetics , Nuclear Proteins/genetics , Proliferating Cell Nuclear Antigen/genetics , STAT3 Transcription Factor/genetics , Twist-Related Protein 1/genetics , Up-Regulation/genetics , Animals , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Epithelial Cells/metabolism , Female , HEK293 Cells , Humans , Janus Kinase 2/genetics , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphatidylinositol 3-Kinases/genetics , Promoter Regions, Genetic/genetics , Signal Transduction/genetics , Urinary Bladder Neoplasms/geneticsABSTRACT
Foram estudados, retrospectivamente, 1.054 prontuários de pacientes com 1.054 fraturas do fêmur proximal (fraturas do colo do fêmur, transtrocanterianas e subtrocanterianas), tratadas no Hospital Escola da Faculdade de Medicina do Triângulo Mineiro (HE-FMTM/Uberaba, MG), de janeiro de 1985 a março de 2000. Os seguintes atributos foram analisados e comparados com a literatura pertinente: idade, sexo, estado civil, cor, profissäo, procedência, mecanismo do trauma, diagnóstico, lado acometido, doenças associadas, tratamento e tempo de internaçäo. Os resultados revelaram concordância com a literatura, havendo predomínio de fraturas em pacientes do sexo feminino, com idade média de 68 anos e cinco meses, causadas por trauma mínimo, sendo raras em negros. As fraturas transtrocanterianas foram mais comuns, seguidas pelo colo do fêmur e subtrocanterianas, näo existindo predominância em relaçäo ao lado acometido. O tempo médio de internaçäo foi de 10 dias. A maioria dos pacientes era casada e procedente do mesmo município. As doenças associadas principais foram: déficits visuais, osteoporose e hipertensäo arterial. O tratamento na maioria foi a osteossíntese. Concluiu-se que, para diminuir a incidência e o impacto social dessas fraturas, a prevençäo das doenças associadas e as medidas para evitar acidentes domésticos em idosos seriam procedimentos efetivos e pouco dispendiosos, pois o conhecimento e a prevençäo dos fatores de risco evitariam a maior parte dos casos de fraturas.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Femoral Fractures/epidemiology , Aged, 80 and over , Femoral Fractures/diagnosis , Prevalence , Risk FactorsABSTRACT
O câncer de cérvix uterino é uma doença freqüente em países em desenvolvimento. No Brasil ele só perde em freqüência para o câncer de pele entre a populaçÝo feminina e a maioria das lesöes sÝo diagnosticadas no estádio III. Nos casos avançados da doença pode ser indicado o uso da quimioterapia neo-adjuvante. Revisando a literatura médica nacional e estrangeiraa nos últimos 10 anos sobre o tema, observou-se uma grande variaçäo nos resultados obtidos. A resposta completa oscilou entre 0 e 68,9 porcento (média de 20 porcento) e a resposta total variou de 23 a 91,8 porcento (média de 60 porcento). A quimioterapia neo-adjuvante aumentou a ressecabilidade das lesöes na maioria dos artigos revisados. Quanto à sobrevida em 3 anos, a maior parte das pesquisas demonstrou uma diferença estatisticamente significativa a favor das pacientes submetidas à quimioterapia em relaçäo ao grupo-controle. Näo há comprovaçäo consistente do aumento da sobrevida em 5 anos.
