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- Jönsson, Göran B, et al.
(författare)
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The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.
- 2012
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Ingår i: Cancer Research. - 1538-7445. ; 72:16, s. 4028-4036
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Tidskriftsartikel (refereegranskat)abstract
- Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status.
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- Magnusson, Marie V, et al.
(författare)
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Pentoxifylline and vitamin E treatment for prevention of radiation-induced side-effects in women with breast cancer : a phase two, double-blind, placebo-controlled randomised clinical trial (Ptx-5)
- 2009
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Ingår i: European Journal of Cancer. - Oxford : Elsevier. - 0959-8049 .- 1879-0852. ; 69:24, s. 740-740
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Tidskriftsartikel (refereegranskat)abstract
- Background: A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation-induced fibrosis. The aim of the present study is to investigate if the same drugs could prevent radiation-induced side-effects in women with breast cancer.Patients and methods: A randomised, placebo-controlled, double-blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with 400 mg pentoxifylline t.i.d. or placebo, in combination with 100 mg vitamin E t.i.d,, starting 1-3 months after the completion of radiotherapy. The primary end-point was passive abduction of the shoulder, and the secondary end-point was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623.Results: 83 patients were included in the study; 42 in the pentoxifylline + vitamin E group and 41 in the placebo + vitamin E group. Both treatments were generally well tolerated. Seven patients were withdrawn from the treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion, patients had impaired passive abduction of the shoulder. During treatment, both the groups improved significantly. Median improvement from baseline was 3.7 degrees (p = 0.0035) on pentoxifylline and was 9.4 degrees (p = 0.0041) in the placebo group, but no difference between the groups was detected (p = 0.20). Arm volumes increased over time in the placebo group (1.04%), but not on pentoxifylline (0.50%), and differed significantly between the groups (p = 0.0172).Conclusions: The combination of pentoxifylline and vitamin E was safe and may be used for the prevention of some radiation-induced side-effects. (C) 2009 Elsevier Ltd. All rights reserved.
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- Persson, Mikael, et al.
(författare)
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[Lu-177]pertuzumab : Experimental therapy of HER-2-expressing xenografts
- 2007
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:1, s. 326-331
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Tidskriftsartikel (refereegranskat)abstract
- Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter Lu-177, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [Lu-177]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [Lu-177]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and Lu-177-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [Lu-177]pertuzumab for therapy.
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- Saal, Lao, et al.
(författare)
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PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
- 2005
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Ingår i: Cancer Research. - 1538-7445. ; 65:7, s. 2554-2559
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Tidskriftsartikel (refereegranskat)abstract
- Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate WIN is critical for tumorigenesis in a significant fraction of breast cancers and that loss Of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.
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