Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

Abstract

Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, β and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kβ. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.

Manic Fringe Promotes a Claudin-Low Breast Cancer Phenotype through Notch-Mediated PIK3CG Induction

“…3). Encoding the γ catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase, PIK3CG has recently been shown to promote breast cancer growth and metastasis (17,18). We verified that knockdown of Mfng caused a dramatic decrease in Pik3cg level, as well as reduced Akt phosphorylation in CLBC cells (Fig.…”

“…Pik3cg is aberrantly expressed in many invasive human breast tumors and its expression level correlates with metastatic potential of breast cancer cell lines (18). Here we demonstrate that Pik3cg is a downstream effector of Mfng-facilitated Notch activation.…”

“…Here we demonstrate that Pik3cg is a downstream effector of Mfng-facilitated Notch activation. Previous studies indicate that Pik3cg may promote migration and invasion of breast cancer cells, while inhibiting anoikis (17,18). Our results suggest that Pik3cg contributes to breast cancer aggressiveness not only by promoting cell migration, but also by maintaining cancer stemness.…”

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…In regard to cancer, p110γ overexpression can transform chicken embryo fibroblasts in culture via a Ras-dependent mechanism (49). Also, increased PI3Kγ signaling is implicated in the development of breast, pancreatic, and brain tumors or Kaposi sarcoma by promoting tumor inflammation and metastasis (50)(51)(52)(53)(54). Despite the tumorigenic properties of PI3Kγ, Stat1 inhibits cell proliferation and tumorigenesis, suggesting the presence of control pathways mediated by Stat1 to counteract PI3Kγ-mediated tumorigenesis.…”

Molecular determinants of PI3Kγ-mediated activation downstream of G-protein–coupled receptors (GPCRs)

“…Overexpression of p110γ induces cell transformation (7). Pharmacological inhibition of p110γ can prevent tumor growth and spreading by blocking myeloid-derived tumor inflammation and by suppressing breast cancer cell invasion (8)(9)(10). Depletion of p110γ or its regulatory subunit p101 inhibited primary tumor formation and metastasis by murine epithelial carcinoma cells (11).…”