Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor

Abstract

The molecular mechanisms by which ovarian hormones stimulate growth of breast tumors are unclear. It has been reported previously that estrogens activate the signal-transducing Src/p21 ras /Erk pathway in human breast cancer cells via an interaction of estrogen receptor (ER) with c-Src. We now show that progestins stimulate human breast cancer T47D cell proliferation and induce a similar rapid and transient activation of the pathway which, surprisingly, is blocked not only by anti-progestins but also by anti-estrogens. In Cos-7 cells transfected with the B isoform of progesterone receptor (PR B ), progestin activation of the MAP kinase pathway depends on co-transfection of ER. A transcriptionally inactive PR B mutant also activates the signaling pathway, demonstrating that this activity is independent of transcriptional effects. PR B does not interact with c-Src but associates via the N-terminal 168 amino acids with ER. This association is required for the signaling pathway activation by progestins. We propose that ER transmits to the Src/p21 ras /Erk pathway signals received from the agonist-activated PR B . These findings reveal a hitherto unrecognized cross-talk between ovarian hormones which could be crucial for their growth-promoting effects on cancer cells.

Rapid signalling by androgen receptor in prostate cancer cells

“…This is in agreement with reports of ER and PR activating MAP kinase through the Ras-Raf-1-MEK pathway (Migliaccio et al, , 1998. In addition, we have shown for the AR that PI3 kinase and PKC also contribute to the DHT-mediated activation of MAP kinase.…”

“…In addition, a number of steroid hormones are reported to rapidly and reversibly activate important intermediates in signal transduction pathways known to trigger cell proliferation (Migliaccio et al, , 1998Endoh et al, 1997;Marcinkowska et al, 1997). For example estrogens activate two members in the family of c-srcrelated tyrosine kinases, c-src and c-yes as well as the MAP kinases Erk-1 and -2 (Di .…”

“…For example estrogens activate two members in the family of c-srcrelated tyrosine kinases, c-src and c-yes as well as the MAP kinases Erk-1 and -2 (Di . Progestins also activate MAP kinase, a reaction that has been correlated with an indirect association of the progesterone receptor (PR) with c-src through the intermediary role of the estrogen receptor (ER) (Migliaccio et al, 1998). Interaction of the PR and ER with c-src either directly or indirectly enhances the kinase activity of this protein which then activates MAP kinase via the Ras-Raf-1 pathway (Castoria et al, 1999).…”

“…We therefore report here a rapid cellular signalling response which appears to be speci®c for the AR. a novel non-conventional mechanism (Migliaccio et al, , 1998Endoh et al, 1997;Marcinkowska et al, 1997). In this study we have asked whether androgens also mediate this response using two primary androgen responsive cells: human genital skin ®broblasts and prostatic stromal cells.…”

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

“…Western blotting using phospho-specific antibodies indicated that EGF stimulation of T47D cells induces phosphorylation of PR Ser294 at 5-10 min, similar to that induced by R5020 at early time points (15,16). Both agents are known to activate MAPKs within 5-15 minutes (25,26). However, EGF is a stronger activator of MAPK relative to progestins at this time point, and liganded PRs are relatively transient, most likely due to the rapid down-regulation of liganded and Ser294 phosphorylated species (14).…”