Membrane
progesterone receptors (mPRs) have been detected in
breast cancer cells and tissues, but their roles in
cancer progression remain unclear. Here, we demonstrate the localization, signaling, and antiapoptotic actions of mPRs in two nuclear
progesterone receptor (PR)-negative
breast cancer cell lines, SKBR3 and MDA-MB-468 (MB468), and mPR expression in human
breast tumor biopsies. mPRα, mPRβ, and mPRγ subtypes were detected in both cell lines as well as in
breast tumor tissues from 13 individuals irrespective of nuclear
steroid receptor expression. Competitive receptor binding studies with a selective PR
ligand,
R5020, and an mPR agonist, Org OD 02-0 confirmed the presence of functional mPRs on both
cancer cell lines.
Progesterone treatment of either cell line caused rapid activation of an inhibitory
G protein, as well as activation of p42/44 MAP
kinase. Treatment with
progesterone or Org OD 02-0 significantly decreased cell death and apoptosis in response to serum
starvation, whereas
testosterone, 17β-estradiol,
dexamethasone, and
R5020 and
RU486 were ineffective.
Progesterone treatment of MB468 cells also increased mitochondrial membrane potential and Akt activity, but no decrease in
caspase 3 activity was observed. Knockdown of mPRα expression in MB468 cells by
siRNA transfection blocked the inhibitory effects of
progesterone on cell death. The results indicate that
progesterone can act through mPRs to inhibit apoptosis in
breast cancer cells. The involvement of mPRs in the development or progression of
breast tumor growth through inhibition of cell death is an intriguing possibility and requires further investigation.