The online version of this article (doi:10.1186/1476-4598-11-61) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
HL initiated, designed the studies, and oversaw the completion of the project. ZP conducted the vast majority of experiments. Briefly, ZP, JCW, JRS, ZH and WZ performed viral transduction studies, EMT analysis, Western blots, transwell migration, cell viability, flow cytometry and other related experiments. RS, and MC provided clinical, pathological, or scientific insights of breast cancer. All authors helped in discussing, reading and proofreading the final manuscript. All authors read and approved the final manuscript.
The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion.
We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting.
We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.
Additional file 1: Dichotomy Effects of Akt Signal on Breast Neoplasm. (DOC 308 KB)12943_2012_1034_MOESM1_ESM.doc
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- Dichotomy effects of Akt signaling in breast cancer
Jennifer Chao Weber
James R Scott
Michael WY Chan
Huey-Jen L Lin
- BioMed Central
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