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National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Sylvia C. Hewitt, National Institute of Environmental Health Sciences, 111 Alexander Drive, MD E4-01, Research Triangle Park, North Carolina 27709. E-mail: curtiss{at}niehs.nih.gov.
The endometrium and mammary glands are both complex tissues comprised of multiple cell types. The endometrium consists of stromal cells that support epithelial cells lining the uterine lumen as well as glandular epithelial structures that emanate from the lumen (1). The mammary gland consists of stromal adipose cells in which branched epithelial ducts develop (2). Both of these tissues are exquisitely sensitive to ovarian steroid hormones first at puberty, during which progesterone and estrogen orchestrate the intricate maturation of the tissues, and then in the adult female during ovarian cycles, throughout establishment and maintenance of pregnancy, and during initiation and sustenance of lactation. The stromal cells in both tissues are thought to secrete paracrine signals that communicate to the epithelial cells (3).
The responses to progesterone and estrogen are initiated by their respective nuclear receptors. In the case of the progesterone receptors (PR), two forms of the PR protein, PRA and PRB, have been identified in tissues and are encoded by the same gene but differ by an extended N-terminal region in PRB (4). In vitro studies have shown that PRA and PRB homodimers and heterodimers each have distinct transcriptional regulatory activities, including PRB-mediated inhibition of PRA and estrogen receptor transcriptional activities (5). The PR isoforms have also been studied in tissues and have been shown to be present in varying ratios by Western blotting, which can distinguish the two by virtue of their different molecular weights. Ablation of both PRs or selective deletion of PRA or PRB has indicated distinct biological roles of the receptors in mouse tissues (4). The full PR knockout (KO) lacks the uterine responses of decidualization and opposition of estrogen-induced hyperplasia. Additionally, the PRKO lacks full mammary epithelial development during pregnancy. The uterine phenotypes are rescued in the PRBKO, which expresses only PRA, indicating that PRA is critical for these uterine responses; whereas the PRAKO recovers the mammary gland development, illustrating the importance of PRB for pregnancy-associated mammary growth. Mouse models in which the mammary tissue selectively overexpresses PRA or PRB transgenes have suggested the importance of maintaining a balance between the isoforms, because the PRB-overexpressing gland lacks ductal elongation, and the PRA-overexpressing gland has ductal hyperplasia and disruption of the basement membrane (6, 7).
From these studies of progesterone response, it is clear that mechanisms must take in to account both the relative levels of the PR isoforms as well as the cell types expressing PRs in tissues to understand biological outcomes. Thus, PRA- and PRB-selective antibodies have been used to evaluate the relative expression of PRA and PRB proteins in individual cells by immunohistochemistry. The relative expression and cellular localization of PRA and PRB in human samples including normal endometrium at different stages of the menstrual cycle, as well as human breast and endometrial cancers, have been evaluated using this approach (8, 9, 10, 11, 12, 13). In this issue, Mote et al. (14) describe the relative expression and colocalization of PRA and PRB proteins in the uterus and mammary gland of cycling mice and further evaluate the effects of ovariectomy and estrogen or progesterone replacement on PR expression. This study augments a previous study describing PRA and PRB in developing adult and pregnant mouse mammary glands (15).
In this issue, Mote et al. (14) make several basic contributions to the field that are of great value because they provide a descriptive standard for evaluation of potential mouse phenotypes. First, a popular approach in the field of hormone response is ovariectomy and hormone replacement, because this approach allows selective control of the hormonal environment. However, the study by Mote et al. shows that the PRA and PRB expression patterns differ greatly between normally cycling and ovariectomized mice. PRA is found exclusively in uterine stromal and myometrial cells in a cycling mouse, whereas there is abundant PRA in the luminal epithelial cells of an ovariectomized uterus. Similarly, ovariectomy diminishes the PR level in the mammary epithelium. This dissimilar pattern of PR isoform expression highlights a shortcoming of the ovariectomized mouse as a biological model of progesterone response. The observations reported by Mote et al. and the lack of normal uterine responses of implantation, decidualization, and inhibition of hyperplasia in the PRAKO (4) lead to the conclusion that these essential uterine functions are largely stroma dependent.
Second, as alluded to above, the uterus and mammary tissues of the mouse are used in many different types of studies. For example, the mouse uterus is useful for study of estrogen or progesterone responses, because it is highly sensitive to both steroids. Investigators often use exogenous agonists, antagonists, or toxicological insults to evaluate biochemical endpoints such as nuclear localization or phosphorylation of proteins isolated from tissue or gene regulation as reflected by RNA levels. Uterine biological responses including growth and establishment and maintenance of pregnancies are often evaluated using experimental approaches that examine biological endpoints of interest, such as uterine weight or tissue histology. Some genetically manipulated mouse models have altered uterine biology, and both biological and biochemical analyses are often used to evaluate sources of phenotypes. Understanding the normal baseline of PRA and PRB cellular localization in mouse tissues provides an important reference for identifying and investigating altered responses in any of these approaches.
In the clinic, studies have indicated colocalization and equal levels of PRA and PRB in human endometrium and breast (8, 11) rather than the selective distribution and predominance of PRA seen in mouse tissues (16). Analysis of invasive breast or endometrial cancers indicates a frequent alteration of PR isoform ratios (11, 12). The approach presented here for analysis of mouse tissues may now be used to determine whether there are also perturbations in PR isoform ratios in mouse tissues that underlie pathologies such as the endometrial lesions in the PTEN +/– model (17) or mammary tumors in MMTV-neu transgenics (18), which could strengthen their significance as models of human cancers.
In addition to the above-described contributions, this study and its predecessors include analysis of an extensive panel of antibodies as regards their cross-reactivity with mouse vs. human PRA and PRB, which will prove to be important for investigators attempting to evaluate clinical or mouse model studies.
Questions that remain for future study include how and why the cell and tissue specificities of the PR isoforms are regulated by ovarian hormones. But for now, adding the where and when to prior studies of "who" (which PR isoform) does what has provided reproductive biologists and cancer researchers more of the basic facts needed to expand and interpret their own investigations.
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Received September 25, 2006.
Accepted for publication September 27, 2006.
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