Modulation of endometrial steroid receptors and growth regulatory genes by tamoxifen.
OBJECTIVE
We investigated tamoxifen's effects on the expression of growth regulatory genes in the endometrium to identify the mechanism by which tamoxifen induces proliferation.


METHODS
Using immunohistochemical techniques, we analyzed 39 endometrial specimens for expression of Ki-67, lactoferrin, transforming growth factor-alpha, tumor necrosis factor receptor-II, adrenomedullin, estrogen receptors, and progesterone receptors. Twenty specimens were obtained from postmenopausal breast cancer patients treated with tamoxifen (20 mg/day) for at least 6 months to include two endometrial adenocarcinoma specimens. Five secretory phase, three proliferative phase, and seven atrophic endometrial specimens were used as controls. In addition, four endometrial adenocarcinoma specimens were reviewed from patients not treated with tamoxifen. Intensity of immunostaining was quantified using digitized imaging techniques.


RESULTS
Overexpression of both estrogen receptors and progesterone receptors, and an elevated proliferative index were the most consistent effects observed in benign endometrial specimens from tamoxifen-treated patients compared with atrophic controls (P <. 003). This staining pattern was also evident in adenocarcinomas from patients who received tamoxifen. Benign endometrium from tamoxifen-treated patients also expressed transforming growth factor-alpha, tumor necrosis factor receptor-II, lactoferrin, and adrenomedullin at levels comparable with those found in proliferative endometrial specimens.


CONCLUSIONS
These data provide further documentation that the uterotropic effects of tamoxifen may be due, at least in part, to the induction of estrogen receptors and progesterone receptors, as well as other genes associated with the proliferative phase. Furthermore, analysis of estrogen receptors, progesterone receptors, and Ki-67 may be useful in identifying postmenopausal individuals on tamoxifen, who are at increased risk for developing endometrial cancer.
Elkas
J
J
Department of Obstetrics and Gynecology, National Naval Medical Center, Bethesda, Maryland, USA. jelkas@ucla.edu
Armstrong
A
A
Pohl
J
J
Cuttitta
F
F
Martínez
A
A
Gray
K
K
D053607:Adrenomedullin; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005809:Genes, Regulator / Q000187:drug effects*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D007781:Lactoferrin / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D019394:Ki-67 Antigen; D010455:Peptides; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018124:Receptors, Tumor Necrosis Factor; D016211:Transforming Growth Factor alpha; D013629:Tamoxifen; D053607:Adrenomedullin; D007781:Lactoferrin