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Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair.

Minami A, Nakanishi A, Ogura Y, Kitagishi Y, Matsuda S - Front Oncol (2014)

Bottom Line: Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses.The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors.Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, Nara Women's University , Nara , Japan.

ABSTRACT
Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration implying that genome stability is sustained on several tumor suppressors. Note that some critical other functions have been omitted for clarity.
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Figure 2: Schematic illustration implying that genome stability is sustained on several tumor suppressors. Note that some critical other functions have been omitted for clarity.

Mentions: Genome stability might be sustained on several tumor suppressors (Figure 2). Loss of PTEN increases cell survival and reduces DNA repair, which may lead to genomic instability and may enhance radiosensitivity. In case of cancer cells that compromise therapeutic success, targeting inhibition of PTEN-related PI3K/AKT/mTOR pathway has been shown to prevent tumorigenesis and progression. Indeed, for example, rapamycin, an mTOR-specific inhibitor, prevents leukemia development in PTEN- mouse models (83, 84). However, the effectiveness of rapamycin may require PTEN deletion or genetic loss of PTEN function. The presence of wild-type PTEN may compromise the efficacy of rapamycin (85). In addition, studies show that mTOR inhibition decreases PTEN transcription and subsequently activates AKT (85). Further detailed mechanistic understanding of the roles of PTEN in DNA repair and DNA damage response in different tissues and cell types will help us fully understand the precise molecular mechanisms by which PTEN maintains genomic stability and contributes to tumor suppression and therapeutic efficacy. PTEN and BRCA1 may be regulated and interact each other at multiple levels including transcription, protein modulation, and protein stability. Understanding the connection between tumor suppressor BRCA1 and PTEN would facilitate the development of effective agents and strategies to better treatment against cancer. The PTEN inhibitor has been shown to effectively activate primordial follicles both in neonatal mouse ovaries and in human ovarian cortical tissues (86, 87). It is important to investigate the functional linkage between PTEN and BRCA1 in those ovarian samples, and elucidation of interaction-specific functions may provide insight into regulatory aspects of these tumor suppressors as well as opportunities for therapeutic intervention. Indeed, the regulation is crucial for the effective design of novel ovarian cancer therapeutics. Further mechanistic studies are needed in order to understand the precise molecular mechanisms for the effective treatment of cancers with PTEN/BRCA1 signal alterations. Targets within this pathway could provide strategies for modulation of PTEN/BRCA1 proteins, which may prove therapeutically beneficial for breast, ovarian, and prostate cancer treatment.


Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair.

Minami A, Nakanishi A, Ogura Y, Kitagishi Y, Matsuda S - Front Oncol (2014)

Schematic illustration implying that genome stability is sustained on several tumor suppressors. Note that some critical other functions have been omitted for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4226230&req=5

Figure 2: Schematic illustration implying that genome stability is sustained on several tumor suppressors. Note that some critical other functions have been omitted for clarity.
Mentions: Genome stability might be sustained on several tumor suppressors (Figure 2). Loss of PTEN increases cell survival and reduces DNA repair, which may lead to genomic instability and may enhance radiosensitivity. In case of cancer cells that compromise therapeutic success, targeting inhibition of PTEN-related PI3K/AKT/mTOR pathway has been shown to prevent tumorigenesis and progression. Indeed, for example, rapamycin, an mTOR-specific inhibitor, prevents leukemia development in PTEN- mouse models (83, 84). However, the effectiveness of rapamycin may require PTEN deletion or genetic loss of PTEN function. The presence of wild-type PTEN may compromise the efficacy of rapamycin (85). In addition, studies show that mTOR inhibition decreases PTEN transcription and subsequently activates AKT (85). Further detailed mechanistic understanding of the roles of PTEN in DNA repair and DNA damage response in different tissues and cell types will help us fully understand the precise molecular mechanisms by which PTEN maintains genomic stability and contributes to tumor suppression and therapeutic efficacy. PTEN and BRCA1 may be regulated and interact each other at multiple levels including transcription, protein modulation, and protein stability. Understanding the connection between tumor suppressor BRCA1 and PTEN would facilitate the development of effective agents and strategies to better treatment against cancer. The PTEN inhibitor has been shown to effectively activate primordial follicles both in neonatal mouse ovaries and in human ovarian cortical tissues (86, 87). It is important to investigate the functional linkage between PTEN and BRCA1 in those ovarian samples, and elucidation of interaction-specific functions may provide insight into regulatory aspects of these tumor suppressors as well as opportunities for therapeutic intervention. Indeed, the regulation is crucial for the effective design of novel ovarian cancer therapeutics. Further mechanistic studies are needed in order to understand the precise molecular mechanisms for the effective treatment of cancers with PTEN/BRCA1 signal alterations. Targets within this pathway could provide strategies for modulation of PTEN/BRCA1 proteins, which may prove therapeutically beneficial for breast, ovarian, and prostate cancer treatment.

Bottom Line: Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses.The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors.Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, Nara Women's University , Nara , Japan.

ABSTRACT
Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.

No MeSH data available.


Related in: MedlinePlus