Figure 7.

Cartoon illustrating the interactions of exogenous and endogenous/aTGFβ that operate in PDAC- and TNBC-derived tumor cells. Left-hand side, the aTGFβ1 forms a regulatory feedforward loop with ERK1/2 to sustain high-level ERK activation. This circuit prevents exogenous TGFβ1 (rhTGFβ1 in vitro or paracrine and stromal cell derived-TGFβ1 in vivo) from inducing growth arrest or cell migration through TβR1/ALK5 via induction of p21^WAF1 (WAF1) or SNAIL, respectively. The aTGFβ1-ERK loop is driven by mutant (m) and wild-type versions of RAS, RAF, or EGFR/Erb-b2 receptor tyrosine kinase 2 (HER2) and additionally through TβRI/ALK5. Exogenous TGFβ1 also transcriptionally up-regulates TGFB1, and the resulting TGFβ1 protein via mutant RAS-ERK signaling can provide feedback inhibition of its own production. Right-hand side, in normal/benign cells, the aTGFβ1-ERK autoregulatory loop is non-functional due to the lack of mutant RAS/RAF proteins or lower expression or activation of TβRI/ALK5, but low-level activation of the aTGFβ1-ERK circuit is eventually achieved through EGFR activation via (wild-type) RAS. Green arrows denote activation or induction and red lines inhibition. Grey-shaded arrows/lines indicate inactivation.