| 711. |
|
|
| 712. |
- Junttila, T T, et al.
(författare)
-
Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells
- 2005
-
Ingår i: Cancer Research. - 1538-7445. ; 65:4, s. 1384-1393
-
Tidskriftsartikel (refereegranskat)abstract
- ErbB1 and ErbB2 receptors are well-characterized targets for anticancer drugs, but the clinical relevance of the related ErbB4 receptor is unknown. Here, we have assessed the clinical significance of the proteolytically cleavable ErbB4 isoforms in breast cancer patients and investigated their functions in vitro. The expression of transcripts encoding the cleavable ErbB4 isoforms associated with estrogen receptor-{alpha} (ER) expression (P < 0.001) and a high histologic grade of differentiation (P ≤ 0.002) in real-time reverse transcription-PCR analysis of 62 breast cancer samples. Despite high ErbB4 mRNA expression levels in a subset of samples, ErbB4 gene amplification was not observed. High ErbB4 protein expression levels, as assessed by immunohistochemistry, associated with a favorable outcome in ER-positive cases from a series of 458 breast cancer patients (P = 0.01), whereas no association between ErbB4 expression and survival was found among women with ER-negative cancer (P = 0.86). However, nuclear ErbB4 immunoreactivity was associated with poor survival as compared with women whose cancer had membranous ErbB4 staining (P = 0.04). In vitro, overexpression of a cleavable ErbB4 isoform in ER-positive breast cancer cells resulted in translocation of a proteolytically released intracellular ErbB4 receptor fragment into the nucleus, as well as, enhanced proliferation, anchorage-independent growth, and estrogen response element–mediated transcriptional activity. These results suggest that the association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription.
|
|
| 713. |
|
|
| 714. |
- Jönsson, Göran B, et al.
(författare)
-
The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.
- 2012
-
Ingår i: Cancer Research. - 1538-7445. ; 72:16, s. 4028-4036
-
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.
|
|
| 715. |
- Jönsson, Marzieh, et al.
(författare)
-
Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas.
- 2002
-
Ingår i: Cancer Research. - 1538-7445. ; 62:2, s. 409-416
-
Tidskriftsartikel (refereegranskat)abstract
- Previous in vitro studies have implied that the Wnt-5a gene plays a role as a tumor suppressor. To explore the clinical relevance of this concept, 96 primary invasive breast carcinomas were stained with a novel anti-Wnt-5a antibody. Loss of Wnt-5a protein expression, evident in 44% of the invasive ductal carcinomas (n = 59), was significantly associated with higher histological grade (P = 0.01) and absence of estrogen (P = 0.003) and progesterone (P = 0.02) receptors. By contrast, loss of Wnt-5a protein in 24% of the invasive lobular carcinomas (n = 37) was not significantly related to any of the variables we investigated. The prognostic value of Wnt-5a for metastatic potential was evaluated by analyzing 83 additional invasive primary ductal carcinomas from patients with a longer follow-up time. We found that Wnt-5a expression was lost in tumors from 78% of the patients with recurrent disease (n = 32) compared with 35% of the recurrence-free patients (n = 51; P < 0.001), and that recurrence-free survival was significantly shorter in the Wnt-5a-negative group (P < 0.001). In multivariate analyses, loss of Wnt-5a expression proved to be an independent and powerful predictor of recurrence after adjustment for lymph node status and tumor size (hazard ratio = 4.8; P = 0.002). Our results show that loss of Wnt-5a increases the risk of early relapse and death because of recurrent ductal breast cancer, findings that support the notion that this protein retains tumor suppressor function by virtue of its effects on cell adhesion and motility.
|
|
| 716. |
|
|
| 717. |
- Kainu, Tommi, et al.
(författare)
-
Detection of Germline BRCA1 Mutations in Breast Cancer Patients by Quantitative Messenger RNA in situ Hybridization
- 1996
-
Ingår i: Cancer Research. - 1538-7445. ; , s. 2912-2915
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in the breast cancer susceptibility gene 1 (BRCA1) may account for one half of all familial breast cancers. Because of the wide spectrum of different germline mutations, identification of BRCA1 mutation carriers using current techniques is laborious and difficult. The majority of the identified mutations, however, lead to aberrant expression of the gene product in tumor tissue, potentially allowing the detection of BRCA1-linked breast cancers using simple histochemical techniques. We performed quantitative mRNA in situ hybridization analysis on archival paraffin-embedded tumor specimens from 25 patients with characterized germline BRCA1 mutations or linkage and from 29 patients with sporadic breast cancers. BRCA1 mRNA levels were invariably low in tumors from BRCA1 mutation carriers. Normal breast epithelium surrounding the BRCA1 tumors showed higher mRNA levels than the tumor tissue, indicating that the low mRNA levels were due to somatic inactivation of the wild-type BRCA1 allele in the tumor tissue. The expression levels in the sporadic tumors were, on average, six times higher than in the BRCA1 tumors (P < 0.0001). The difference allowed identification of BRCA1-mutated and sporadic tumors with more than 95% specificity and sensitivity. We conclude that the analysis of BRCA1 gene expression by mRNA in situ hybridization may be useful in screening for patients with BRCA1-linked breast cancer.
|
|
| 718. |
|
|
| 719. |
|
|
| 720. |
|
|
