Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor.
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 (PRB), progestin activation of the MAP kinase pathway depends on co-transfection of ER. A transcriptionally inactive PRB mutant also activates the signaling pathway, demonstrating that this activity is independent of transcriptional effects. PRB 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 PRB. These findings reveal a hitherto unrecognized cross-talk between ovarian hormones which could be crucial for their growth-promoting effects on cancer cells.
Migliaccio
A
A
Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, II Università di Napoli, Largo S.Aniello a Caponapoli, 2, 80138 Napoli, Italy.
Piccolo
D
D
Castoria
G
G
Di Domenico
M
M
Bilancio
A
A
Lombardi
M
M
Gong
W
W
Beato
M
M
Auricchio
F
F
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D017354:Point Mutation; D011397:Promegestone / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases
D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D013629:Tamoxifen; D004958:Estradiol; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; D011397:Promegestone; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D019950:Mitogen-Activated Protein Kinase 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)