Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients.
Women with hormone dependent breast cancer initially respond to hormone deprivation therapy with tamoxifen or oophorectomy for 12-18 months but later relapse. Upon secondary therapy with aromatase inhibitors, patients often experience further tumor regression. The mechanisms responsible for secondary responses are unknown. We postulated that hormone deprivation induces hypersensitivity to estradiol. Evidence of this phenomenon was provided in a model system involving MCF-7 cells grown in vitro and in xenografts. To determine if the ER transcriptional process is involved in hypersensitivity, we examined the effect of estradiol on ER reporter activity, PgR, PS2, and c-myc as markers and found no alterations in hypersensitive cells. Next, we examined whether MAP kinase may be upregulated in the hypersensitive cells as a reflection of increased growth factor secretion or action. Basal MAP kinase activity was increased both in vitro and in vivo in hypersensitive cells. Proof of principle studies indicated that an increase in MAP kinase activity induced by TGFalpha administration caused a two- to three-fold shift to the left in estradiol dose response curves in wild type cells. Blockade of MAP kinase with PD98059 returned the shifted curve back to baseline. These data suggested that MAP kinase overexpression could induce hypersensitivity. To determine why MAP kinase was increased, we excluded constitutive receptor activity and growth factor secretion by the demonstration that the pure anti-estrogen, ICI 182780, could inhibit MAP kinase activation. We also excluded hypersensitivity to estradiol induced growth factor secretion, and thus MAP kinase activation, since estradiol stimulated MAP kinase at 24, 48, and 72 h at the same concentrations in hypersensitive as in wild type cells. Surprisingly, a series of experiments suggested that MAP kinase increased in hypersensitive cells as a result of estrogen activation via a non-genomic pathway. We examined the classical signal pathway in which SHC is phosphorylated and binds to SOS and GRB-2 to activate Ras, Raf, and MAP kinase. With 5-20 min of exposure, estradiol caused binding of SHC to the estrogen receptor, phosphorylation of SHC, binding of GRB-2 to SOS, and activation of MAP kinase. All of these affects could be blocked by ICI 182780. Taken together, these observations suggest that the cell membrane ER pathway may be responsible for upregulation of MAP kinase and hypersensitivity in cells adapted to estradiol deprivation.
Santen
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R
Division of Endocrinology, University of Virginia Health System, P.O. Box 800379, Jefferson Park Avenue, Charlottesville, VA 22908, USA. rjs5y@virginia.edu
Jeng
M H
MH
Wang
J P
JP
Song
R
R
Masamura
S
S
McPherson
R
R
Santner
S
S
Yue
W
W
Shim
W S
WS
D000222:Adaptation, Physiological; D000818:Animals; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D011506:Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases