Abstract
Loss of Forkhead box P1 (FOXP1) protein expression confers a poor prognosis in sporadic and familial breast cancer patients, and the FOXP1 gene maps to a tumor suppressor locus at chromosome 3p14. Although correlation studies have indicated that FOXP1 has a role in tumor suppression, determination of the regulatory mechanism of FOXP1 is required to establish its function in breast cancer. It has previously been identified that FOXP1 is regulated by estrogen in breast cancer and that treatment with bisphenol A is effective for regulating the transformation of the normal human breast epithelial cell line, MCF-10F. In addition, FOXO-regulated activation of FOXP1 inhibits the apoptosis of MCF-10F cells following tamoxifen and Akt inhibitor VIII administration. The present study indicates that FOXP1 regulation occurs via a PI3K/Akt/p70S6 kinase (p70S6K) signaling pathway. Following treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt, MCF7 and MDA-MB-231 breast cancer cells demonstrated decreased FOXP1 protein expression levels; this result was also observed in the small interfering (si)RNA silencing of Akt. By contrast, overexpression of Akt resulted in increased FOXP1 protein expression levels in the MDA-MB-231 cells compared with the control cell lysates. Furthermore, treatment with rapamycin, a specific inhibitor of the mammalian target of rapamycin/p70S6K cascade, resulted in decreased FOXP1 expression in the MCF7 cells, but not in the MDA-MB-231 cells, which were resistant to rapamycin-induced inhibition. In addition, silencing of p70S6K using siRNA produced a marked decrease in FOXP1 expression. These data indicate that FOXP1 protein expression is regulated by a PI3K/Akt/p70S6K signaling cascade in breast cancer.
Highlights
The phosphatidylinositol 3‐kinase (PI3K)/Akt signaling pathway is associated with variable cellular functions critical to tumor initiation and progression, including proliferation, migration, invasion and metastasis, as well as the acquired endocrine resistance of breast cancer following hormonal therapy [1,2]
Pharmacological inhibition of the PI3K/Akt signaling pathway was initially performed by treating the MCF7, ZR‐75.1 and MDA‐MB‐231 cells with 100 nm wortmannin to elucidate the effect of Akt inhibition on Forkhead box P1 (FOXP1) protein expression levels
FOXP1 is located on the tumor suppressor locus at chromosome 3p14.1, and trisomy of chromosome 3 has been associated with increased FOXP1 expression in mucosa-associated lymphoid tissue lymphoma
Summary
The phosphatidylinositol 3‐kinase (PI3K)/Akt signaling pathway is associated with variable cellular functions critical to tumor initiation and progression, including proliferation, migration, invasion and metastasis, as well as the acquired endocrine resistance of breast cancer following hormonal therapy [1,2]. An important downstream Ser/Thr kinase, performs its functions by activating or inactivating ~200 different downstream targets [3]. One of these downstream targets is p70S6K, a Ser/Thr kinase that is regulated by PI3K/Akt. The roles of p70S6K are not limited to protein translation, but involve the co‐regulation of other cellular responses, such as cell survival, proliferation and migration [4,5,6]. Van Boxtel et al [10] demonstrated that the therapeutic targeting of PI3K/Akt with tamoxifen facilitates the nuclear import of FOXO, inducing FOXP1 protein expression [10]
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