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Diethylstilbestrol‐induced immortalization of human endometrial cells: Alterations in p53 and estrogen receptor
Author(s) -
Rinehart Clifford A.,
Xu Lihui,
Van Le Linda,
Kaufman David G.
Publication year - 1996
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199602)15:2<115::aid-mc4>3.0.co;2-i
Subject(s) - biology , estrogen , diethylstilbestrol , stromal cell , carcinogenesis , estrogen receptor , endocrinology , medicine , cancer research , gene , cancer , genetics , breast cancer
Carcinogenesis is a process requiring multiple steps. Immortalization is one step in this process and may be rate limiting. To further our understanding of estrogen‐induced carcinogenesis, we evaluated diethylstilbestrol (DES)‐induced immortalization of human endometrial stromal cells. This was achieved by assessing at the restrictive temperature the colony‐forming efficiency of cells that were conditionally immortalized with a temperature‐sensitive simian virus 40 large T antigen. Treatment with DES for 1 wk did not increase the immortalization frequency; however, cultures that were treated for 20 wk had a twofold increase in immortalization frequency, and continued treatment for a total of 44 wk produced a threefold increase in immortalization frequency that was dose dependent. DES‐treated restrictive temperature variants (RTVs) but not spontaneous RTVs lost the temperature‐sensitive phenotype. DES‐RTVs also had a shorter doubling time than spontaneous RTVs did. p53 expression was increased in DES‐RTVs, and its localization within the cell was altered. Conversely, expression of the estrogen receptor was decreased in DES‐immortalized cells. These changes in gene expression often occur in estrogen‐related malignancies, and our results are consistent with a causal role for estrogens in these p53 and the estrogen receptor alterations. Immortalization of human cells may be analogous to initiation of rodent cells, and our results suggest that estrogen‐induced alterations in p53 or other genes that regulate life span could contribute to estrogen‐induced initiation. © 1996 Wiley‐Liss, Inc.