Wnt signaling can substitute for estrogen to induce division of ERα-positive cells in a mouse mammary tumor model

Abstract

The interaction of estrogen with the estrogen receptor (ER, principally ERα) induces growth of human breast tumor cells. In contrast, ERα-positive cells have been described as non-dividing cells in normal breast (though estrogen stimulation of ERα cells directs the division of neighboring cells). However, there is a small sub-population of cells in normal mammary tissue that are ERα-positive, that can divide, and therefore share this property with human breast tumor cells. In order to investigate their pattern of growth regulation, we measured the fraction of dividing ERα + cells during normal growth and compared that to glands stimulated by oncogenic Wnt effectors. First, we found there was no difference between the rate of division of ERα + cells and ERα − cells, whether the population was responding to estrogen or Wnt mitogens. The proportion of dividing ERα + mammary epithelial cells was increased (10×) in response to pregnancy, and similar increases were observed in response to ectopic Wnt signaling. We propose that Wnt signaling can substitute for estrogen to drive total population growth (that includes ERα + cells). Although the E-ERα-derived mitogenic response is situated in a minority of the luminal cells, and the Wnt-LRP5/6-derived mitogenic response is situated in a minority of basal cells, overall, the growth response of the mammary epithelial population is remarkably similar.