The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

Friedenson, Bernard

doi:10.1186/1471-2407-7-152

Cited by 166 publications

(89 citation statements)

References 67 publications

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“…BRCA1 is a tumor suppressor (Duncan et al ., 1998; Yoshida and Miki, 2004), which is responsible for repairing damaged DNA (Chen et al ., 2011). Women with an abnormal BRCA1 gene have up to an 80% higher risk of developing breast cancer (Friendenson, 2007). We determined that restoring BRCA1 in HCC 1937 cells, which is a BRCA1‐deficient line, represses Pol III gene transcription (Zhong et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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“…Apoptosis is a complex cellular process and can be regulated by intrinsic and extrinsic stimulations (Kerr et al 1972;Murphy et al 2000;Dejean et al 2006). The intrinsic pathway occurs during embryogenesis, either by hormone induction or injurious stimuli such as radiation, toxins, and hypoxia (van't Veer et al 2002;Friedenson 2007). Apoptosis is controlled by the BCL-2 family of proteins, which are divided into two major categories of factors: anti-and proapoptotic.…”

Section: Discussionmentioning

confidence: 99%

“…Study on FAK knockout mice model indicated that it plays a key role in determining the rate of cell migration (Laghi et al 1985). BRCA1 is a human tumor suppressor gene normally expressed in breast and other tissues and is involved in DNA double-strand break repair (Friedenson 2007). Abnormal expression of FAK and BRCA1 is closely related to breast cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

Effects and mechanism of flavonoids from Astragalus complanatus on breast cancer growth

Zhang

Zhu

Zhang

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Flavonoids from Astragalus complanatus R.Br (FAC) had anticancer effects on many tumor cells. The current study was performed to evaluate the effects of FAC on human breast cell proliferation, apoptosis, and metastasis, as well as their active mechanism. Cell viability and growth were detected using the cell counting kit (CCK)-8 assay in vitro. Assay of FAC on induced breast cancer mortality was counted as survival time of nude mice after breast cell line inoculation. The effect of FAC on cell invasion was investigated by an optimization assay that contains a 96-well Boyden chamber with wells precoated with BME at three different concentrations. The mechanism of its action on apoptosis and metastasis was determined by related gene detection. Proliferation of three breast cell lines was inhibited with FAC treatment in a dose-dependent manner. Survival time of nude mice with breast cancer cell inoculation also was prolonged with increasing FAC dose. Metastasis in FAC-treated breast cells was also significantly inhibited. Real-time polymerase chain reaction (PCR) assay demonstrated that apoptosis-related BCL-2 and caspase-9 gene expression was consistent with their phenotype change. Metastasis-related FAK and BRCA1 gene expression was inversely related to FAC treatment. Western blot analysis indicated that BCL-2 and FAK proteins were reduced, whereas caspase-9 and BRCA1 proteins were increased with a higher dose of FAC treatment. These data suggested that FAC has an important role in breast cancer growth and metastasis suppression in vitro and in vivo. Its active mechanism involves promoting programmed cancer cell death and regulates metastasis-related gene expression.

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“…Mis-repaired double strand breaks can result showing up in cancers as DNA rearrangements such as translocations, deletions, inversions, and amplifications. Risks for cancers associated with DNA rearrangements thus increase [Friedenson 2007]. Risks for a subset of leukemias and lymphomas are greatly elevated over the risks in normal individuals, up to nearly 2000 fold [Friedenson 2007].…”

Section: Leukemias and Lymphomasmentioning

confidence: 99%

Should the Status of the Pathway Mediated by BRCA1 and BRCA2 be Evaluated Before Selecting Cancer Chemotherapy Drugs?

Friedenson

2007

CPG

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This review brings together evidence to show that chemotherapy agents that cause DNA double strand breaks have increased success in treating model cancers with deficits in the pathway containing BRCA1/2 proteins. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates error-free repair of DNA double strand breaks. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements and deletions of DNA segments are more likely. This mechanism contributes to the gross chromosomal rearrangements found in a large majority of human cancers. In many cancers, gene rearrangements and deletions are believed to be critical events so a compromised BRCA pathway increases cancer risk in general. Mutation specifically of the BRCA1 or the BRCA2 gene increases risk as much as about 8 times for subsets of numerous cancers including stomach, pancreas, prostate, colon, etc. as reported in epidemiologic studies. Moreover, inactivating virtually any gene within a model for the BRCA pathway increases risk up to nearly 2000 fold for a subset of leukemias and lymphomas that frequently contain gene rearrangements.In tumor cells, the status of the BRCA pathway may be important during chemotherapy. Some chemotherapy agents cause chromosome breaks as they destroy tumor cells but other types of chemotherapy depend on different mechanisms. A damaged BRCA pathway may make subgroups of tumors unable to correctly repair broken chromosomes. Because normal error-free repairs are no longer assured, sensitivity to chemotherapy drugs that cause DNA double strand breaks should especially increase.The end result specifying tumor resistance vs. tumor sensitivity to chemotherapy is complicated and may be modified by additional mechanisms. Nevertheless this review of the literature shows that the status of the BRCA pathway is a broadly useful criterion in selecting chemotherapy agents for model tumors derived from a variety of different organs. These preclinical models show real gains depending on the chemotherapy regimen selected. If the models are appropriate predictors in cancer patients, then identifying patients more likely to respond to a given chemotherapy agent should minimize serious adverse effects and prolong survival times.

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The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

Cited by 166 publications

References 67 publications

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Effects and mechanism of flavonoids from Astragalus complanatus on breast cancer growth

Should the Status of the Pathway Mediated by BRCA1 and BRCA2 be Evaluated Before Selecting Cancer Chemotherapy Drugs?

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