Compelling evidence has been provided to support the notion that p38 gamma is a gene that maintains oncogenic properties but does not promote metastasis of breast cancer, suggesting that special caution is needed to define a metastasis-promoting gene.
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, UV irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis, and autophagy. Four p38 MAP kinases, p38α (MAPK14), β (MAPK11), γ (MAPK12/ERK6), and δ (MAPK13/SAPK4), have been identified, and their functions in cancer remain elusive. Recently, several studies from different groups revealed potential functional role of p38γ MAPK in breast cancer. However, their results are not consistent, suggesting further clarification is necessary in this scenario.
We read with great interest the report by Rosenthal and his colleagues investigating the role and mechanism of p38γ MAPK in breast cancer motility and metastasis.1 The authors used a small hairpin (shRNA) technique to knockdown p38γ MAPK expression in MDA-MB 231 cells. They found that p38γ MAPK knockdown dramatically altered breast cancer cell motility and cell invasion in vitro and inhibited lymphomatic metastasis in vivo. They also demonstrated that the regulation of RhoC GTPase, the change in cytoskeletal architecture, and a novel, leading-edge behavior due to p38γ MAPK knockdown, could be the underlying mechanism behind those activities. Based on these data, they concluded that p38γ MAPK is a breast cancer metastasis-promoting gene. This conclusion is different from our observation that p38γ MAPK is an oncogenic property-maintaining gene in breast cancer.2
The reasons we question p38γ MAPK as a metastasis-promoting gene are as follows: first, p38γ MAPK knockdown can only be used to determine if p38γ MAPK is required for breast cancer motility or metastasis. Our group examined the effect of ectopic expression of p38γ MAPK in different breast cancer cell lines, and found that p38γ MAPK overexpression could not significantly promote cell migration, invasion, and metastasis.2 In addition, p38γ MAPK phosphorylation was observed in some established overexpression cell models, which are comparable to the endogenous p38γ MAPK phosphorylation in highly metastatic cells (Fig. 1). This data suggests that ectopic expression of p38γ MAPK has similar activity compared with endogenous p38γ MAPK in the examined cells. Taken together, our results indicate that p38γ MAPK alone is not enough to promote metastasis, and that other genetic alterations are needed to co-operate p38γ MAPK for metastasis induction. This notion is further supported by several recent publications.3,4
Figure 1. Expression of p-p38γ in a panel of breast cancer cells detected by western blot. P38γ-V5 was ectopically expressed in poorly metastatic breast cancer cells HMLE, EpRas, MCF7, and 67NR. SUM159 and MDA231 are highly metastatic breast cancer cell lines. Ectopic expression of p38γ-V5 leads to expression of p-p38γ in HMLE, EpRas, MCF7, and 67NR cells, which is comparable to the endogenous p-p38γ level in SUM159 and MDA231 cells. β-actin is used as the protein loading control.
Second, Rosenthal and his colleagues did not show any results of p38γ MAPK knockdown in cell proliferation and tumor growth. Our observation revealed that p38γ MAPK knockdown in 4T1 cells led to significant decrease of cell proliferation, a phenomenon also observed in Hela cells.5 Concomitantly, we observed decreased cell migration and invasion in 4T1 cell with p38γ MAPK depletion. Furthermore, a xenografting experiment showed a significant shrinkage of tumor formation along with marked decrease of lung metastasis, suggesting that the decreased cell migration and invasion or metastasis is mostly due to the effect of p38γ MAPK on cell survival.2
Despite of the disagreement of how to interpret the experimental results, there are numerous consistencies in these two independent studies. For example, both studies agree p38γMAPK expression is correlated with basal-like breast cancer and is associated with overall survival of breast cancer patients. Thus, p38γ MAPK is a promising therapeutic target for basal-like breast cancer.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Footnotes
Previously published online: www.landesbioscience.com/journals/cc/article/25333
References
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