Interestingly, even though Six1 overexpressing luminal cells are uniquely dependent on TGF b signaling to improve TIC populations in vitro, they may be no extra dependent than handle cells on MEK ERK signaling to induce some TIC traits in vitro, and for tumor initia tion in vivo. Instead, Six1 overexpression increases the magnitude of MEK ERK signaling. These information make it possible for us to speculate the MEK inhibitor, AZD6244, may be an enticing drug to target the luminal breast cancer TICs in any cells by which MEK ERK signaling is lively, but that Six1 overexpressing cells could need elevated ranges with the drug to accom modate the enhanced MEK ERK signaling observed in people cells. The mechanism by which Six1 activates MEK ERK signaling is still unknown. It really is identified that TGF b can activate the MEK ERK pathway by a non canonical pathway.
On the other hand, whilst our information indicate that Six1 could possibly partially regulate MEK ERK signaling downstream of TGF b, it’s not original site clear that this mechan ism is solely accountable. As an alternative, we favor the hypoth esis that Six1 regulates MEK ERK signaling by way of TGF b signaling likewise as via regulating additional pathways, and that the induction of TGF b signaling and MEK ERK signaling together contribute to your skill of Six1 to induce TICs. The two TGF b signaling and MEK signaling have already been implicated in EMT and TICs, and consequently, Six1 upregula tion of those pathways is consistent with the ability of Six1 to impart a TIC phenotype. Without a doubt, TGF b signaling is definitely an inducer of EMT and TICs within a range of cells and, in regular murine mammary gland epithelial cells, MEK ERK signaling is needed for TGF b induced EMT. MEK ERK sig naling has also been implicated during the induction of stem cell traits independent of TGF b signaling.
Such as, inhibition of MEK ERK signaling results in dif ferentiation of human embryonic stem cells and human pluripotent stem cells into functional CD34 progenitor cells, suggesting that MEK ERK signaling hop over to here is impor tant for your servicing of stem cell properties. Furthermore, MEK ERK signaling has become implicated not merely in regular stem cells, but in TICs. Ultimately, our information demonstrate that Six1 expression in human tumors correlates the two with activated TGF b sig naling and with activated ERK. It should be mentioned the Six1 antibody used in these experiments was gener ated towards a conserved region of Six1 and it may hence cross react with other Six household members. consequently we are able to only confidently state that Six loved ones member expression correlates with activated ERK. On the other hand, as Six1 is strongly correlated with prognosis in human breast cancers, and as its overexpression is observed in as countless as 50% to 90% of breast cancers, it’s very likely that the staining is reflective of Six1 expression.