Fig. 1.

Development of endocrine therapy resistance in ERα-expressing breast cancers and a new proposed treatment paradigm. (A) E2 (blue triangles) promotes breast tumorigenesis by binding ERα and recruiting CoActs to stimulate canonical ERα target genes that promote growth. Xiao et al. (14) show that E2-liganded ERα activates expression of CSK to create a negative feedback loop to suppress oncogenesis mediated by the SFKs/PAK2 axis by inhibitory phosphorylation of SFKs (red circled “P”). Bent arrows indicate gene transcription. (B) Upon endocrine therapy targeting E2-bound ERα (main text), the expression of canonical ERα target genes, as well as the CSK-mediated negative feedback loop, is inhibited. The loss of CSK allows for more active SFKs/PAK2 kinase signaling (observed by activating phosphorylation of SFKs and PAK2, green circled “P”) and, with time, induces resistance to endocrine therapy by “bypassing” the negative feedback loop. Importantly, Xiao et al. (14) show that a PAK2 inhibitor effectively suppresses tumor growth in immunodeficient mice transplanted with CSK knockout cells.