Impact of progesterone receptor on cell-fate decisions during mammary gland development

Mammary epithelium contains lineage-limited progenitors that give rise to c ells that form distinct morphological structures, ducts vs. lobules, depend ing on the endocrine status of the female. Progesterone signaling through p rogesterone receptor (PR) is essential for lobulo-alveolar development that accompanies pregnancy, but not far ductal growth accompanying puberty. PR exists in two molecular forms, A and B, and an imbalance in the native rati o of the two isoforms can lead to alterations in PR signaling. Indeed, as w e reported previously, in transgenic mice carrying additional A form of PR, mammary development is abnormal, characterized by excessive lateral ductal branching. This suggests that alterations in PR signaling may have importa nt consequences to mammary development, particularly with regard to ductal vs. alveolar growth. To test this further, we created transgenic mice carry ing additional B form of PR and report that mammary development in these mi ce is also abnormal, characterized by inappropriate alveolar growth. More i mportantly, these mammary glands, on serial transplantation, undergo a prem ature arrest in ductal growth without any alteration in the potential for l obulo-alveolar growth. Such an arrest in ductal growth does not occur with transgenics carrying additional A farm of PR. These studies. therefore, pro vide strong evidence to indicate that PR signaling may be of paramount impo rtance for appropriate cell-fate decisions during normal mammary developmen t and also that this requires a regulated expression of the two isoforms.