Cell Proliferation of Estrogen-Sensitive Cells: The Case for Negative Control*

THAT the administration of estrogens to oophorectomized vertebrates results in the proliferation of certain cell types in secondary sex organs has been acknowledged for decades (1). Whether 17β-estradiol (E2) acts directly or indirectly on the proliferation of such target cells has been widely debated without reaching a conclusive answer. Since a definitive answer to this question cannot be obtained using whole animals, researchers explored models in which rodent target tissues have been explanted in culture (2–4). However, these experimental designs were not sufficiently discriminatory to conclude whether proliferation was due directly to the estrogen interaction with the cell that was stimulated or whether intermediate steps among cell types or within cells were responsible for the effect observed (1–10). During the 60's and 70's renewed interest in characterizing the proliferative response of estrogen target tissues in whole animal models became apparent as the concept of the estrogen receptor, or estrophilins, was developed during this period (11–14). The identification of this discrete cellular marker of target cells was assumed by many to establish a direct causal relationship between estrogen and proliferation (15). Interaction with estrophilins became the obligatory step in this relationship. Cell functions thought to be regulated by estrophilins included synthesis of specific proteins (PRL, ovalbumin, conalbumin, gonadotropins, etc.) and enzymes that are important for cell proliferation (thymidine kinase, DNA polymerase, ornithine decarboxylase, etc.) (16–18). This generalization was implied within the original concepts offered by Jensen whereby estrogen target cells were defined by their estrophilin content (15). There is now general agreement that estrophilins do play an essential regulatory role in the synthesis of cell-type specific proteins, but their role in proliferation of estrogen target cells remains controversial (5). Observations which argue against a direct role of estrophilins in this context include 1) cells containing significant levels of estrophilins do not proliferate when estrogens are administered to oophorectomized animals (19); 2) cells in organs not considered typical targets (the kidney, for example) develop estrogen-sensitive tumors when an estrogen pellet is implanted in the host (20); and 3) organs not considered to be estrogen targets contain cell populations with estrophilins (19, 20). Nevertheless, many researchers consider estrophilins as direct, obligatory mediators of both cell-type specific protein synthesis and cell proliferation (21–25).