Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth.
Cross talk between the steroid hormone receptors for estrogen and progesterone (PR) and the ErbB family of receptor tyrosine kinases appears to be a hallmark of breast cancer growth, but its underlying mechanism remains poorly explored. Here we have highlighted signal transducer and activator of transcription 3 (Stat3) as a key protein activated by heregulin (HRG), a ligand of the ErbB receptors, through co-opted, ligand-independent PR function as a signaling molecule. Stat3 activation was an absolute requirement in HRG-induced mammary tumor growth, and targeting Stat3 effectively inhibited growth of breast cancer cells with activated HRG/ErbB-2 and PR. Our findings unravel a novel potential therapeutic intervention in PR- and ErbB-2-positive breast tumors, involving the specific blockage of PR signaling activity.
Proietti
Cecilia J
CJ
Instituto de Biología y Medicina Experimental, CONICET, Obligado 2490, Buenos Aires 1428, Argentina.
Rosemblit
Cinthia
C
Beguelin
Wendy
W
Rivas
Martín A
MA
Díaz Flaqué
María Celeste
MC
Charreau
Eduardo H
EH
Schillaci
Roxana
R
Elizalde
Patricia V
PV
D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020890:Neuregulin-1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor