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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 depiction of the integrative model of tumor suppressors signaling including PTEN and BRCA1. Examples of molecules known to act on DNA damage response, cell proliferation, and cell cycle via the regulatory pathways are shown. Note that some critical pathways have been omitted for clarity.
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Figure 1: Schematic depiction of the integrative model of tumor suppressors signaling including PTEN and BRCA1. Examples of molecules known to act on DNA damage response, cell proliferation, and cell cycle via the regulatory pathways are shown. Note that some critical pathways have been omitted for clarity.

Mentions: Germline mutations in the breast cancer susceptibility gene 1 (BRCA1) extensively increase the risk of breast and ovarian cancers (1, 2). BRCA1-related tumorigenesis may be mainly caused by increased DNA damage and decreased genome stability that is a major hallmark of cancer (3). To maintain genomic integrity, cells are equipped with committed sensors to monitor DNA repair and/or to impose damaged cells into apoptotic cell death (4). Although functional roles of BRCA1 may include the regulation of DNA damage repair, cell cycle progression, and maintenance of genomic integrity, the precise function of the BRCA1 gene as a tumor suppressor is still not clear. It has been shown that BRCA1 deficiency activates the AKT oncogenic signaling pathway (5). Also, activation of the phosphoinositide 3-kinase (PI3K) is often associated with the BRCA1-related breast cancers in clinical sample (6). The PI3K/AKT pathway might have an essential role in the proliferation of malignant tumor cells related to the BRCA1 functions (Figure 1). BRCA1 can downregulate AKT activation via the direct physical interaction (5, 7). In addition, AKT activation inversely correlates with the BRCA1 expression in human breast cancers (8). Moreover, BRCA1 negatively regulates the PI3K/AKT pathway in breast cancer cells (9). Phosphatase and tensin homolog on chromosome 10 (PTEN) is a dual protein/lipid phosphatase that inhibits the PI3K/AKT pathway, whose inhibition eventually reduces cell growth and cell proliferation (10, 11). The PTEN is also a tumor suppressor molecule and seems to protect from bad prognosis of several cancers. In other words, absence of PTEN worsens prognosis in early stages of cancer (12, 13). Furthermore, germ-line mutations of PTEN are the cause of PTEN hamartoma tumor syndromes (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, Proteus-like syndrome) with increased risk for the development of cancers (14). The PTEN has been shown to be involved in an intricate network of interactions with other molecules (Figure 1). In this review, we summarize the current research and our view of how PTEN and BRCA1 function with their partners to transduce signals downstream and what are the implications for cancer-associated biology.


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 depiction of the integrative model of tumor suppressors signaling including PTEN and BRCA1. Examples of molecules known to act on DNA damage response, cell proliferation, and cell cycle via the regulatory pathways are shown. Note that some critical pathways have been omitted for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic depiction of the integrative model of tumor suppressors signaling including PTEN and BRCA1. Examples of molecules known to act on DNA damage response, cell proliferation, and cell cycle via the regulatory pathways are shown. Note that some critical pathways have been omitted for clarity.
Mentions: Germline mutations in the breast cancer susceptibility gene 1 (BRCA1) extensively increase the risk of breast and ovarian cancers (1, 2). BRCA1-related tumorigenesis may be mainly caused by increased DNA damage and decreased genome stability that is a major hallmark of cancer (3). To maintain genomic integrity, cells are equipped with committed sensors to monitor DNA repair and/or to impose damaged cells into apoptotic cell death (4). Although functional roles of BRCA1 may include the regulation of DNA damage repair, cell cycle progression, and maintenance of genomic integrity, the precise function of the BRCA1 gene as a tumor suppressor is still not clear. It has been shown that BRCA1 deficiency activates the AKT oncogenic signaling pathway (5). Also, activation of the phosphoinositide 3-kinase (PI3K) is often associated with the BRCA1-related breast cancers in clinical sample (6). The PI3K/AKT pathway might have an essential role in the proliferation of malignant tumor cells related to the BRCA1 functions (Figure 1). BRCA1 can downregulate AKT activation via the direct physical interaction (5, 7). In addition, AKT activation inversely correlates with the BRCA1 expression in human breast cancers (8). Moreover, BRCA1 negatively regulates the PI3K/AKT pathway in breast cancer cells (9). Phosphatase and tensin homolog on chromosome 10 (PTEN) is a dual protein/lipid phosphatase that inhibits the PI3K/AKT pathway, whose inhibition eventually reduces cell growth and cell proliferation (10, 11). The PTEN is also a tumor suppressor molecule and seems to protect from bad prognosis of several cancers. In other words, absence of PTEN worsens prognosis in early stages of cancer (12, 13). Furthermore, germ-line mutations of PTEN are the cause of PTEN hamartoma tumor syndromes (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, Proteus-like syndrome) with increased risk for the development of cancers (14). The PTEN has been shown to be involved in an intricate network of interactions with other molecules (Figure 1). In this review, we summarize the current research and our view of how PTEN and BRCA1 function with their partners to transduce signals downstream and what are the implications for cancer-associated biology.

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