# Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway

## TL;DR

Gamma tocotrienol, a form of vitamin E, kills cancer stem cells by targeting SHP2 and disrupting the RAS/ERK pathway.

## Contribution

Gamma tocotrienol specifically targets SHP2 and the RAS/ERK pathway in cancer stem cells, offering a new therapeutic approach.

## Key findings

- Gamma tocotrienol inhibits mammosphere and sphere growth in a dose-dependent manner.
- Gamma tocotrienol reduces SHP2 activity and RAS/ERK signaling without affecting self-renewal genes.
- Gamma tocotrienol shows promise as a natural drug for targeting breast cancer stem cells.

## Abstract

There is increasing evidence supporting the concept of cancer stem cells (CSCs), which are responsible for the initiation, growth and metastasis of tumors. CSCs are thus considered the target for future cancer therapies. To achieve this goal, identifying potential therapeutic targets for CSCs is essential.

We used a natural product of vitamin E, gamma tocotrienol (gamma-T3), to treat mammospheres and spheres from colon and cervical cancers. Western blotting and real-time RT-PCR were employed to identify the gene and protein targets of gamma-T3 in mammospheres.

We found that mammosphere growth was inhibited in a dose dependent manner, with total inhibition at high doses. Gamma-T3 also inhibited sphere growth in two other human epithelial cancers, colon and cervix. Our results suggested that both Src homology 2 domain-containing phosphatase 1 (SHP1) and 2 (SHP2) were affected by gamma-T3 which was accompanied by a decrease in K- and H-Ras gene expression and phosphorylated ERK protein levels in a dose dependent way. In contrast, expression of self-renewal genes TGF-beta and LIF, as well as ESR signal pathways were not affected by the treatment. These results suggest that gamma-T3 specifically targets SHP2 and the RAS/ERK signaling pathway.

SHP1 and SHP2 are potential therapeutic targets for breast CSCs and gamma-T3 is a promising natural drug for future breast cancer therapy.

The online version of this article (doi:10.1186/s12885-015-1614-1) contains supplementary material, which is available to authorized users.