Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium

Kenneth Nephew, Tara C. Polek, Sohaib A. Khan

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c- fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c- fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c- fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.

Original languageEnglish (US)
Pages (from-to)219-224
Number of pages6
JournalEndocrinology
Volume137
Issue number1
DOIs
StatePublished - 1996
Externally publishedYes

Fingerprint

Proto-Oncogenes
Tamoxifen
Epithelium
Estrogen Receptor Modulators
Myometrium
Hypertrophy
Epithelial Cells
jun Genes
Pharmaceutical Preparations
fos Genes
Messenger RNA
Endometrium
Oncogenes
Uterus
In Situ Hybridization
Estrogens
Therapeutics
Pathology
Breast Neoplasms
Injections

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium. / Nephew, Kenneth; Polek, Tara C.; Khan, Sohaib A.

In: Endocrinology, Vol. 137, No. 1, 1996, p. 219-224.

Research output: Contribution to journalArticle

Nephew, Kenneth ; Polek, Tara C. ; Khan, Sohaib A. / Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium. In: Endocrinology. 1996 ; Vol. 137, No. 1. pp. 219-224.
@article{5b6c7f406d754f558ffdfb62b8682d15,
title = "Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium",
abstract = "The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c- fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c- fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c- fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.",
author = "Kenneth Nephew and Polek, {Tara C.} and Khan, {Sohaib A.}",
year = "1996",
doi = "10.1210/en.137.1.219",
language = "English (US)",
volume = "137",
pages = "219--224",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "1",

}

TY - JOUR

T1 - Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium

AU - Nephew, Kenneth

AU - Polek, Tara C.

AU - Khan, Sohaib A.

PY - 1996

Y1 - 1996

N2 - The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c- fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c- fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c- fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.

AB - The use of the antiestrogen tamoxifen for breast cancer management, although generally well tolerated, is linked to an increase in uterine pathologies in a high number of postmenopausal women receiving the drug. This effect is thought to be due to estrogenic stimulation of the uterine endometrium by the antiestrogen; however, the molecular mechanism underlying the uterotrophic activity of tamoxifen and the uterine cellular compartments that respond to the drug have not been clearly established. In this study, we determined which of the several uterine tissues (myometrium, stroma, and luminal and glandular epithelium) demonstrated chronic overexpression of c- fos and the jun proto-oncogenes in response to tamoxifen. Uteri from tamoxifen-treated, castrated rats were examined histologically, and cell type-specific expression of c-fos, c-jun, jun-B, and jun-D was assessed using in situ hybridization. Treatment with tamoxifen resulted in uterine luminal and glandular epithelial hypertrophy and basally located nuclei by 36 h. Extreme uterine glandular and luminal epithelial cell hypertrophy persisted 7 days after administration of the drug. Expression of c-fos and jun-B messenger RNA was first detected in the luminal and glandular epithelial at 12-36 h post tamoxifen injection. Seven days after tamoxifen treatment, c- fos and jun-B messenger RNA levels were lower but still evident in the uterine endometrial epithelium. Tamoxifen completely repressed constitutive expression of c-jun in the uterine luminal epithelial cells by 12 h but, unlike estrogen, did not induce c-jun expression in the uterine myometrium. Expression of jun-D in the uterine glandular and luminal epithelia was observed at 12 h but not at 24 h post tamoxifen. These results support our working hypothesis that persistent overexpression of cellular oncogenes c- fos and jun-B in the uterine endometrial epithelium may contribute to the molecular mechanism underlying the uterine toxicity associated with chronic tamoxifen treatment.

UR - http://www.scopus.com/inward/record.url?scp=0030038898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030038898&partnerID=8YFLogxK

U2 - 10.1210/en.137.1.219

DO - 10.1210/en.137.1.219

M3 - Article

C2 - 8536616

AN - SCOPUS:0030038898

VL - 137

SP - 219

EP - 224

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 1

ER -