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PI3K mutations in breast cancer: prognostic and therapeutic implications.

Mukohara T - Breast Cancer (Dove Med Press) (2015)

Bottom Line: The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer.Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations.Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center and Division of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Japan.

ABSTRACT
The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (∼30%) observed, along with protein loss of PTEN. Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations. Although many issues remain unconfirmed, some have been carved in stone by the level of consistency they have shown among studies: 1) PIK3CA mutations are most likely to be observed in ER-positive/HER2-negative tumors, and are associated with other good prognostic characters; 2) PIK3CA mutations can coexist with other PI3K-enhancing mechanisms, such as HER2 amplification and PTEN protein loss; 3) PIK3CA mutations are potentially a good prognostic marker; 4) PIK3CA may predict a poorer tumor response to trastuzumab-based therapies, but its impact on disease-free survival and overall survival is uncertain; and 5) based on reports of early clinical trials, PIK3CA mutations do not guarantee a dramatic response to PI3K inhibitors. Collectively, there is currently no sufficient evidence to recommend routine genotyping of PIK3CA in clinical practice. Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited.

No MeSH data available.


Related in: MedlinePlus

Class I PI3K pathway. RTK activation allows p85 to interact with RTK directly or via adaptor proteins, which recruits PI3K to the membrane. On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3. PTEN catalyzes the conversion of PIP3 to PIP2. PIP3 is further recognized by AKT and PDPK1. The connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue. For maximal activation of AKT, phosphorylation of the S473 residue by mTORC2 is required. AKT phosphorylates GSK3, FOXO1, MDM2, BIM, and BAD. AKT also phosphorylates and inactivates TSC2, which subsequently allows RHEB to activate mTORC1.
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f2-bctt-7-111: Class I PI3K pathway. RTK activation allows p85 to interact with RTK directly or via adaptor proteins, which recruits PI3K to the membrane. On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3. PTEN catalyzes the conversion of PIP3 to PIP2. PIP3 is further recognized by AKT and PDPK1. The connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue. For maximal activation of AKT, phosphorylation of the S473 residue by mTORC2 is required. AKT phosphorylates GSK3, FOXO1, MDM2, BIM, and BAD. AKT also phosphorylates and inactivates TSC2, which subsequently allows RHEB to activate mTORC1.

Mentions: On RTK activation, p85 interacts directly with RTK or via adaptor proteins, and the resulting PI3K is recruited to the membrane (Figure 2).4 In addition to RTKs, RAS, which triggers MAPK pathways, can also directly bind to and activate PI3K (Figure 2).5 On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3.4,5 In physiological conditions, the intracellular concentration of PIP3 is meticulously regulated by PTEN, which catalyzes the conversion of PIP3 to PIP24,5 As a result, PTEN functions as a negative regulator of PI3K. PIP3 is further recognized by AKT and PDPK1.4,5 Connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue.4 Maximal activation of AKT requires phosphorylation of the S473 residue by PDPK2, and mTORC2 mainly works as PDPK2.4 AKT phosphorylates several cellular proteins, GSK3, FOXO1, MDM2, and BAD (Figure 2).5 In addition, AKT phosphorylates and inactivates TSC2, which allows RHEB to activate mTORC1 (Figure 2).5 These AKT signalings result in enhanced growth, antiapoptosis, cell-cycle progression, and translation (Figure 2).4,5


PI3K mutations in breast cancer: prognostic and therapeutic implications.

Mukohara T - Breast Cancer (Dove Med Press) (2015)

Class I PI3K pathway. RTK activation allows p85 to interact with RTK directly or via adaptor proteins, which recruits PI3K to the membrane. On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3. PTEN catalyzes the conversion of PIP3 to PIP2. PIP3 is further recognized by AKT and PDPK1. The connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue. For maximal activation of AKT, phosphorylation of the S473 residue by mTORC2 is required. AKT phosphorylates GSK3, FOXO1, MDM2, BIM, and BAD. AKT also phosphorylates and inactivates TSC2, which subsequently allows RHEB to activate mTORC1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440424&req=5

f2-bctt-7-111: Class I PI3K pathway. RTK activation allows p85 to interact with RTK directly or via adaptor proteins, which recruits PI3K to the membrane. On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3. PTEN catalyzes the conversion of PIP3 to PIP2. PIP3 is further recognized by AKT and PDPK1. The connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue. For maximal activation of AKT, phosphorylation of the S473 residue by mTORC2 is required. AKT phosphorylates GSK3, FOXO1, MDM2, BIM, and BAD. AKT also phosphorylates and inactivates TSC2, which subsequently allows RHEB to activate mTORC1.
Mentions: On RTK activation, p85 interacts directly with RTK or via adaptor proteins, and the resulting PI3K is recruited to the membrane (Figure 2).4 In addition to RTKs, RAS, which triggers MAPK pathways, can also directly bind to and activate PI3K (Figure 2).5 On the cell membrane, inhibitory regulation of p85 to 110 is canceled, and PI3K becomes active as a kinase. Subsequently, PI3K catalyzes the conversion of PIP2 to PIP3.4,5 In physiological conditions, the intracellular concentration of PIP3 is meticulously regulated by PTEN, which catalyzes the conversion of PIP3 to PIP24,5 As a result, PTEN functions as a negative regulator of PI3K. PIP3 is further recognized by AKT and PDPK1.4,5 Connection of PIP3 to PDPK1 and AKT allows the physical interaction of PDPK1 and AKT, which leads to activation of AKT by phosphorylation of the T308 residue.4 Maximal activation of AKT requires phosphorylation of the S473 residue by PDPK2, and mTORC2 mainly works as PDPK2.4 AKT phosphorylates several cellular proteins, GSK3, FOXO1, MDM2, and BAD (Figure 2).5 In addition, AKT phosphorylates and inactivates TSC2, which allows RHEB to activate mTORC1 (Figure 2).5 These AKT signalings result in enhanced growth, antiapoptosis, cell-cycle progression, and translation (Figure 2).4,5

Bottom Line: The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer.Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations.Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center and Division of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Japan.

ABSTRACT
The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (∼30%) observed, along with protein loss of PTEN. Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations. Although many issues remain unconfirmed, some have been carved in stone by the level of consistency they have shown among studies: 1) PIK3CA mutations are most likely to be observed in ER-positive/HER2-negative tumors, and are associated with other good prognostic characters; 2) PIK3CA mutations can coexist with other PI3K-enhancing mechanisms, such as HER2 amplification and PTEN protein loss; 3) PIK3CA mutations are potentially a good prognostic marker; 4) PIK3CA may predict a poorer tumor response to trastuzumab-based therapies, but its impact on disease-free survival and overall survival is uncertain; and 5) based on reports of early clinical trials, PIK3CA mutations do not guarantee a dramatic response to PI3K inhibitors. Collectively, there is currently no sufficient evidence to recommend routine genotyping of PIK3CA in clinical practice. Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited.

No MeSH data available.


Related in: MedlinePlus