These data indicate that regulation between the ERalpha and PI3K/AKT2 pathway (ERalpha-PI3K/AKT2-ERalpha) may play an important role in pathogenesis of human breast cancer and could contribute to ligand-independent breast cancer cell growth.
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.
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.
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.
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.
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.
Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type.
Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients.
The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate (PIP(3)) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP(3) homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene.
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.
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.
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.
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.