Strikingly, both ovarian and breast cancer cells are selectively sensitive to pharmacologic and genetic manipulation of the PI3K pathway, making molecular therapeutics targeting this pathway particularly attractive approaches for these cancers.
Isoform-specific neutralization of PI3K isoforms in breast cancer cell lines (by PI3K antibody microinjection or a p110delta-selective pharmacological inhibitor) demonstrated that p110delta is the most important class IA PI3K in the regulation of epidermal growth factor-driven motility in vitro, controlling the directionality and, to a lesser extent, the speed of migration.
Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer.
Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7.
This study was undertaken to investigate the role of PI3K/Akt signaling pathway in metal resistance in human breast cancer epithelial cells with different p53 and estrogen receptor status.
To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels.
The data presented here identify an alternative survival signal that is dependent on PLD and mTOR and is active in a breast cancer cell line where the PI3K survival pathway is not active.
Some of the PIK3CA mutations were detected in the early lesions of breast cancer carcinoma, hepatocellular carcinoma, and gastric carcinomas, suggesting that PIK3CA mutation may occur independent of stage of the tumors.
These data indicate that mutations of PIK3CA play an oncogenic role in substantial fractions of ovarian and breast carcinomas, and in consideration of mutation of other components of the PI3K-AKT pathway in both tumor types, confirm the major oncogenic role of this pathway in ovarian and breast carcinomas.
Fifteen breast cancer cell lines and 92 primary breast tumors (33 with matched normal tissue) were used to check somatic mutation and gene copy number of PIK3CA.
Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients.
PIK3CA mutation was an independent factor for worse survival in breast cancer patients with non-amplified erbB2 (RR = 2.6, 95%CI [1.2-5.5], p = 0.016).
Transfection of PI3K siRNA in breast cancer cells resulted in a significant decrease in cell viability and induction of apoptosis irrespective of their estrogen receptor alpha (ERalpha) or ErbB2 status.
The incidence of point mutations in PIK3CA, the A3140G substitution in particular, in Singapore breast cancers are among the most frequent reported to date for any gene in breast cancer.