TY - JOUR
T1 - Mutations in the phosphatidylinositol 3-kinase pathway
T2 - Role in tumor progression and therapeutic implications in breast cancer
AU - Miller, Todd W.
AU - Rexer, Brent N.
AU - Garrett, Joan T.
AU - Arteaga, Carlos L.
N1 - Funding Information:
This work was supported by the National Institutes of Health K99CA142899 (TWM), K08CA143153 (BNR), Breast Cancer Specialized Program of Research Excellence (SPORE) P50CA98131, Vanderbilt-Ingram Cancer Center Support Grant P30CA68485; a grant from the Breast Cancer Research Foundation (CLA); American Cancer Society Clinical Research Professorship Grant CRP-07-234 (CLA) and Postdoctoral Fellowship 118813-PF-10-070-01-TBG (JTG); the Department of Defense BC093376 (JTG) and BC087465 (BNR); the Lee Jeans Translational Breast Cancer Research Program (CLA); and Stand Up to Cancer/ American Association for Cancer Research Dream Team Translational Cancer Research Grant SU2C-AACR-DT0209 (CLA).
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.
AB - Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.
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U2 - 10.1186/bcr3039
DO - 10.1186/bcr3039
M3 - Review article
C2 - 22114931
AN - SCOPUS:80755127903
SN - 1465-5411
VL - 13
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 6
M1 - 224
ER -