Mammary epithelial cells of PR-A transgenic mice exhibit distinct alterations in gene expression and growth potential associated with transformation

Abstract

Expression of the 'A' and 'B' forms of progesterone receptor (PR), in an appropriate ratio is critical for normal mammary development. As such, mammary glands of PR-A transgenic mice, carrying additional 'A' form of PR as transgene, exhibit morphological and histological characteristics associated with transformation. Accordingly, in the present studies, we analyzed these mammary glands for the presence of transformed epithelial cells by examining for alterations in gene expressions and growth potential, known to be associated with different stages of transformation. These studies reveal that, in the aberrant mammary epithelial structures, there is a decrease in p21 expression, an increase in cyclin D1 expression accompanied by an increase in cell proliferation, and a decrease in estrogen receptor alpha (ER alpha). In mammary ducts with normal histology, there is a decrease in p21 expression without an elevation in cyclin D1 expression or cell proliferation or a decrease in ER alpha expression. Treatment of PR-A transgenics with anti-progestin, mifepristone, has no effect on cell proliferation, cyclin D1 or ER alpha expression in the aberrant epithelial structures. In contrast, mifepristone restored the loss of p21 expression in the epithelial cells of both the ducts with normal histology and aberrant structures. Parallel studies reveal no apparent differences between the mammary glands of wild-type and PR-B transgenic mice, which carry additional PR 'B' form. Accordingly, we conclude that (i) mammary glands of PR-A transgenics contain at least two distinct populations of transformed epithelial cells, (ii) the epithelial cell population in the ducts with normal histology contain presumptive immortalized cells, indicative of early stages of transformation, (iii) the aberrant epithelial structures contain later stages of transformation associated with hyperplasias/pre-neoplasias and (iv) the transformation of mammary epithelial cells in PR-A transgenics might be due to a misregulation in progesterone action resulting from overexpression of PR 'A' form.

Differential expression and regulation of progesterone receptor isoforms in rat and mouse pituitary cells and LβT2 gonadotropes

“…While most PR-target genes were not sensitive to the ratio change, progestin responsiveness was acquired in a subpopulation of gene targets involved in a distinct functional role: cell shape and adhesion (Graham et al 2005). Similar findings have been reported for ductal growth and epithelial transformations in mammary glands of transgenic mice carrying a change in the balance of the native ratio of A:B due to overexpression of PR-A (Shyamala et al 2000, Chou et al 2003.…”

Significance of progesterone receptor-A and -B expressions in endometrial adenocarcinoma

“…Rose showed that mutation of the p53 gene was associated with the absence of PR [4]. Also, Chou et al reported that cyclin D1 expression was up-regulated in mammary epitherial cells in PR-A transgenic mice [34]. However, cyclin D1 expression was inversely correlated with PR-A in our study.…”

Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice

“…BrdU-positive cells were analyzed in paraffin-embedded sections as described previously [9]. Briefly, paraffin sections were deparaffinized and rehydrated prior to antigen retrieval and treatment with specified antibodies.…”

“…Studies using the molecular markers for transformation, as defined by Medina [8], revealed that these mammary glands contained at least two distinct populations of transformed epithelial cells. The ducts with normal histology contain cells resembling immortalized cells, while hyperplasias consist of cells in later stages of transformation associated with early preneoplasias [9]. …”