It is suggested that the phosphatidylinositol 3-kinase (PI3K/Akt) pathway may lead to tamoxifen (Tam) resistance in the estrogen receptor-alpha (ER-alpha)-positive breast cancer cell line, MCF-7.
Our results suggest that PI3K inhibitors should target both p110alpha and p110beta catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER(+) breast cancer.
These results support the notion that combination therapies of doxorubicin (and possibly other chemotherapeutics) with inhibitors of elements of the PI3K pathway are a realistic possibility for future breast cancer therapy, which could lead to reduced side-effects, but that this could be dependent on the genetic background of each breast cancer.
This study showed that two ER+ human breast carcinoma cell lines derived from MCF-7 (MVLN cells) that have acquired under OH-Tamoxifen selection two distinct phenotypes of endocrine resistance both displayed constitutive activation of the PI3K/Akt and MAPK pathways.
Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling.
Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.
PIK3CA, encoding the PI3K catalytic subunit, is the oncogene exhibiting a high frequency of gain-of-function mutations leading to PI3K/AKT pathway activation in breast cancer.
Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
We used a large panel of breast cancer cell lines and in vivo xenograft models to identify candidate predictive biomarkers for a selective inhibitor of class I PI3K that is currently in clinical development.
Our study also suggests that the combination of DSF and a PI3K inhibitor may offer a new combinational treatment model for breast cancer, particularly for those with PIK3CA mutations.
This review provides an overview of the most recent patents, of pre-clinical and clinical studies of inhibitors targeting the different members and/or activators of the PI3K/Akt/mTOR pathway, used alone or in combination with other targeted agents for the treatment of breast cancer.
In univariate analysis, PI3K pathway aberrations were associated with death from breast cancer; however, this relationship was not maintained in multivariate analysis.
HER2 amplification and PIK3CA mutation were validated as biomarkers for sensitivity to the single-agent phosphoinositide 3-kinase (PI3K) inhibitor, GDC-0941, in breast cancer models.
Her2-induced signaling pathways include MAPK and PI3K/Akt, of which the latter has been shown to be critical for Her2(+) breast cancer cell growth and survival.
The common activation of the PI3K pathway in breast cancer has led to the development of compounds targeting the effector mechanisms of the pathway including selective and pan-PI3K/pan-AKT inhibitors, rapamycin analogs for mTOR inhibition, and TOR-catalytic subunit inhibitors.
These results show that formononetin causes cell cycle arrest at the G0/G1 phase by inactivating IGF1/IGF1R-PI3K/Akt pathways and decreasing cyclin D1 mRNA and protein expression, indicating the use of formononetin in the prevention of breast cancer carcinogenesis.
Many genetic and epigenetic alterations have been described, affecting a relatively small number of signaling pathways (PI3K, NK-κB, FGF, etc.) and thus several molecular subtypes of breast cancer have been identified.