Combined phospho-Akt and PTEN expressions associated with post-treatment hysterectomy after conservative progestin therapy in complex atypical hyperplasia and stage Ia, G1 adenocarcinoma of the endometrium.
Young patients with complex atypical hyperplasia (CAH) or stage Ia, G1 adenocarcinoma (IaG1) of the endometrium, who desire to preserve fertility, can select the conservative therapy by oral progestin, medroxyprogesterone acetate (MPA). However, conservative treatments involve potential risks of progression and recurrence. In an attempt to find out molecular markers for sensitivity to MPA, we performed immunohistochemical analysis of PTEN, phospho-Akt, p53, ER and PgR in MPA-treated 31 cases with CAH or IaG1. Eleven of 12 cases (92%) with CAH and 15 of 19 cases (79%) with IaG1 demonstrated an initial complete response, while five patients underwent hysterectomy due to no response. Four of 11 responders (36%) with CAH and five of 15 responders (33%) with IaG1 later developed relapse. Five of nine patients (56%) with CAH and three of 11 patients (27%) with IaG1 became pregnant after infertility treatment. Immunohistochemical analysis revealed that phospho-Akt expression was significantly decreased by MPA administration (p=0.002). Furthermore, combination of two factors, weak phosho-Akt or PTEN-null expression, was found to be significantly associated with receiving hysterectomy (p=0.04), while each factor showed a trend without statistical significance (p=0.07 and 0.2, respectively). Strong expression of both ER and PgR significantly correlated with successful pregnancy after infertility treatment following complete response to MPA (p=0.02). Our observations in vivo suggest that anti-tumor action of MPA may be mediated by dephosphorylation of Akt, and that immunohistochemical evaluation of phospho-Akt and PTEN may be able to predict the outcome of MPA therapy.
Minaguchi
Takeo
T
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. minaguchit-tky@umin.ac.jp
Nakagawa
Shunsuke
S
Takazawa
Yutaka
Y
Nei
Tomomi
T
Horie
Koji
K
Fujiwara
Toshihiro
T
Osuga
Yutaka
Y
Yasugi
Toshiharu
T
Kugu
Koji
K
Yano
Tetsu
T
Yoshikawa
Hiroyuki
H
Taketani
Yuji
Y
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000284:Administration, Oral; D000328:Adult; D003131:Combined Modality Therapy; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000627:therapeutic use; D004714:Endometrial Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007150:Immunohistochemistry; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D011372:Progestins / Q000008:administration & dosage / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D003271:Contraceptive Agents, Female; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D017258:Medroxyprogesterone Acetate; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human