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Review
. 2011;13(6):224.
doi: 10.1186/bcr3039. Epub 2011 Nov 1.

"V体育平台登录" Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer

Todd W Miller  1 , Brent N Rexer, Joan T Garrett, Carlos L Arteaga
Affiliations
Review

Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer

Todd W Miller (V体育2025版) et al. Breast Cancer Res. 2011.

Abstract

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 VSports手机版. 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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Figures

Figure 1
Figure 1
Diagram of the phosphatidylinositol 3-kinase signaling pathway. Tumor promoters and suppressors are labeled in pink and blue, respectively. Nodes targeted by drugs in clinical development are shown in red. AMPK, AMP-activated protein kinase; GPCR, G-protein-coupled receptor; GSK3, glycogen synthase kinase 3; INPP4B, inositol polyphosphate-4-phosphatase, type II; LKB1, liver kinase B1; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP1, phosphatidylinositol monophosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.
Figure 2
Figure 2
Inhibition of phosphatidylinositol 3-kinase/mammalian target of rapamycin abrogates lapatinib resistance in HER2+ breast cancer cells. (a) BT-474 and SKBR3 cells were serum-starved for 3 days, then treated with or without 1 μM lapatinib or 250 nM BEZ235 for 2 days. Cells were fixed, stained using the ApoBrdU kit (Phoenix Flow Systems), and analyzed by flow cytometry. Cells were considered apoptotic if they exhibited sub-G1 levels by propidium iodide staining, and/or high fluorescein isothiocyanate (FITC)-bromodeoxyuridine (BrdU) labeling. Representative plots are shown, and the percentage of apoptotic cells (mean of triplicates ± standard deviation) is noted in each panel; blue, live; red, dead. (b) BT474 and SKBR3 cells were selected for long-term growth in the presence of 2 μM lapatinib to generate resistant cells [83]. Parental and lapatinib-resistant cells were treated with or without 250 nM BEZ235 in growth medium (lapatinib-resistant cells were maintained in 2 μM lapatinib). Media and drugs were replenished every 2 to 3 days. Cell viability was measured after 5 to 6 days by WST1 assay (Roche). Data are presented as percentage parental control for each cell line, mean of triplicates ± standard deviation. *P < 0.05 by Bonferroni post-hoc test compared to parental control.
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