BRCA1 Regulates Gene Expression for Orderly Mitotic Progression

Bae, Insoo; Rih, Jeong Keun; Kim, Hee Jeong; Kang, Hyo Jin; Haddad, Bassem R.; Kirilyuk, Alexander; Fan, Saijun; Avantaggiati, Maria Laura; Rosen, Eliot M.

doi:10.4161/cc.4.11.2152

Cited by 63 publications

(54 citation statements)

References 38 publications

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“…38 BRCA1 has been implicated in the spindle assembly checkpoint, such that down-regulation of BRCA1 causes disruption of the mitotic spindle. [39][40][41] This may account for resistance to the microtubule-interfering agent paclitaxel in cells with inhibited endogenous BRCA1 expression. 5,39,42 Therefore, preclinical data implies that patients with low levels of BRCA1 may benefit from single-agent chemotherapy with a platinum drug, whereas those with high levels may benefit from a single-agent taxane.…”

Section: Discussionmentioning

confidence: 99%

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Weberpals

Garbuio²,

O'Brien³

et al. 2008

Intl Journal of Cancer

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This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p 5 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p 5 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p 5 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro. ' 2008 Wiley-Liss, Inc.Key words: BRCA1; ERCC1; sporadic ovarian cancer; DNA repair; predictive marker Epithelial ovarian cancer (OC) is generally diagnosed at advanced stage resulting in a 5-year survival of only 20-30%. The standard treatment of OC is surgical debulking followed by platinum and taxane chemotherapy. Although 70% of patients with advanced disease initially respond to the first-line regimen, early recurrences and platinum resistance are common obstacles in the management of this disease. Identifying reliable predictors of response and the use of novel therapeutic agents to enhance platinum efficacy are needed to improve the management of OC. Platinum resistance is multifactorial, 1 and an important mechanism of resistance is increased tolerance to platinum-DNA damage and enhanced repair of damaged DNA. In a variety of malignancies including OC, enhanced expression of the DNA repair proteins, Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1), have correlated with resistance to platinum. [2][3][4][5][6] In vitro models have shown that targeting the expression of both BRCA1 and ERCC1 sensitizes cells to platinum-based chemotherapeutic agents, suggesting a potential clinical application to help overcome platinum resistance in OC.Mutations in the BRCA1 tumor suppressor gene are ...

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Section: Discussionmentioning

confidence: 99%

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Weberpals

Garbuio²,

O'Brien³

et al. 2008

Intl Journal of Cancer

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“…42 This result is not inconsistent with our data, since BRCA1 and p53 are known to physically interact, with BRCA1 acting as a coactivator for p53. 43,44 Interestingly, it was recently demonstrated that BRCA1 also positively regulates the expression of Mad2, 41 another potent inhibitor of the APC/C activity 20 and those of other genes implicated in the mitotic spindle checkpoint, 45 emphasizing BRCA1 requirement in the spindle assembly checkpoint control.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

Chabalier¹,

Lamare²,

Racca³

et al. 2006

Cell Cycle

151

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BRCA1 germline mutations predispose women to early onset, familial breast and ovarian cancer. BRCA1 has been recently implicated in the cellular response to agents that disrupt the mitotic spindle. In this report, we studied BRCA1 contribution to paclitaxel response in MCF-7 breast cancer cells. We show that MCF-7 cells transfected with BRCA1 siRNA display a significant increase in resistance to paclitaxel compared with the control cells. We next demonstrate that downregulation of BRCA1 reduces the mitotic index and triggers premature cyclin B1 degradation and decrease in Cdk1 activity following paclitaxel treatment, suggesting that BRCA1 downregulation results in precocious inactivation of the spindle checkpoint. These findings were confirmed by showing that BRCA1 downregulation induces premature sister-chromatids separation in MCF-7 cells following spindle damage. Furthermore, we show that BRCA1 up-regulates the expression of the protein kinase BubR1, essential component of the functional spindle checkpoint, whose downregulation is known to result in paclitaxel resistance in MCF-7 cells. Altogether, our findings support the notion that downregulation of BRCA1 expression mediates paclitaxel resistance through premature inactivation of spindle checkpoint in MCF-7 breast cancer cells. They link BRCA1 to the mitotic checkpoint that plays an essential role in the maintenance of chromosomal stability.

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“…It is not surprising that the EGFRvIII expressing, PTEN-deficient glioblastoma cells also were the most proliferative. Many of the hub genes identified here (ASPM, BUB1, HEK, STK6, NEK2, PTTG1, PRC1, KNSL2, CCNB1, CDC2, and CDC20) also have been shown to be downstream of other key molecular lesions such as BRCA1 in breast cancer (42) or the human papilloma virus proteins E6͞E7 in patients with cervival cancer (for which a ''proliferation cluster'' of 123 genes associated with HPV E6͞E7 in clinical samples strikingly overlapped with the glioblastoma mitosis͞cell cycle module; P ϭ 2.2 ϫ 10 Ϫ16 ) (43). In addition, there was a highly significant overlap with genes that have been shown to be highly overexpressed in high grade breast cancer (P ϭ 3.6 ϫ 10 Ϫ75 ) (44).…”

Section: Gm1600-aspm Sirna Cell Proliferationmentioning

confidence: 99%

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target

Horvath

Zhang²,

Carlson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

594

585

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Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n ‫؍‬ 55 and n ‫؍‬ 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the ''metasignature'' for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers. epidermal growth factor receptor vIII ͉ Glioblastoma ͉ modules ͉ weighted gene coexpression network analysis ͉ network-based screening

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BRCA1 Regulates Gene Expression for Orderly Mitotic Progression

Cited by 63 publications

References 38 publications

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target

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