Modulation of ER phosphorylation on serine 118 by endocrine therapy: a new surrogate marker for efficacy.
BACKGROUND
Phosphorylation of serine 118 (ser118) has been reported to be involved in the activation of estrogen receptor (ER). In the present study, we evaluated whether endocrine therapy modulated ER phosphorylation on ser118.


METHODS
We carried out a tissue microarray that included 80 primary breast tumors obtained before the administration of endocrine therapy. A second tissue microarray included 52 tumors obtained after endocrine therapy from the same patients. Immunostainings were carried out for ER, Pser118ER, Her2, insulin growth factor receptor (IGFR), p21-activated kinase 1 (PAK1), pMAPK, bcl2 and progesterone receptor.


RESULTS
Pser118ER staining was higher in Her2- (P = 0.06), IGFR- (P = 0.0002) and pMAPK-expressing tumors (P = 0.001). The level of ER phosphorylation was not different according to the occurrence of clinical tumor response (P = 0.16). Pser118ER expression was significantly reduced by endocrine therapy. The mean Pser118ER score was 163 [standard deviation (SD) 81] before endocrine therapy and 80 (SD 90) after endocrine therapy (P = 0.0001, paired t-test). The magnitude of Pser118ER decrease was higher in tumors that responded to endocrine therapy (mean decrease 128, SD 86) as compared with refractory tumors (mean decrease 38, SD 130) (P = 0.017, t-test).


CONCLUSIONS
These findings suggest that endocrine therapy modulates ER on ser118. Pser118ER immunostaining could be used as surrogate marker to monitor treatment efficacy.
Zoubir
M
M
Translational Research Unit, UPRES EA035, Université Paris XI, Institut Gustave Roussy, Villejuif; Breast Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif.
Mathieu
M C
MC
Department of Pathology, Institut Gustave Roussy, Villejuif.
Mazouni
C
C
Laboratory of translational research, Marseille University, Marseille, France.
Liedtke
C
C
Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, USA; Department of Gynecology and Obstetrics, University of Muenster, Muenster, Germany.
Corley
L
L
Department of Pathology Research, The University of Texas, MD Anderson Cancer Center, Houston.
Geha
S
S
Department of Pathology, Institut Gustave Roussy, Villejuif.
Bouaziz
J
J
Translational Research Unit, UPRES EA035, Université Paris XI, Institut Gustave Roussy, Villejuif.
Spielmann
M
M
Breast Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif.
Drusche
F
F
Department of Pathology, Institut Gustave Roussy, Villejuif.
Symmans
W F
WF
Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, USA.
Delaloge
S
S
Translational Research Unit, UPRES EA035, Université Paris XI, Institut Gustave Roussy, Villejuif; Breast Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif.
Andre
F
F
Translational Research Unit, UPRES EA035, Université Paris XI, Institut Gustave Roussy, Villejuif; Breast Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif. Electronic address: fabrice.andre@igr.fr.
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D013629:Tamoxifen; D012694:Serine; D017526:Receptor, IGF Type 1