Human breast cell proliferation and its relationship to steroid receptor expression

The steroidal regulation of proliferation and differentiation in the rodent mammary gland is well described, but how ovarian hormones regulate these processes in the human remains poorly understood. To investigate this, we developed the athymic nude mouse model in which intact normal human breast tissue is grafted subcutaneously and treated with estrogen and/or progesterone at human physiological serum levels. We demonstrated, first, that estrogen and not progesterone is the major epithelial cell mitogen in the adult non-pregnant, non-lactating breast, second, that estrogen induces progesterone receptor (PR) expression and, third, that PR expression is maximally induced at low estrogen concentrations while a higher amount of estrogen was required to induce proliferation. These data raised the question of whether one cell type possessed differential responses to high and low estrogen concentrations or whether PR expression and proliferation occurred in two cell populations. Using double-label immunofluorescence, we demonstrated that steroid receptor expression and cell proliferation (Ki67 antigen) occurred in separate cell populations in normal human breast epithelium, and that cells expressing the estrogen receptor-alpha (ERalpha) invariably contained the PR. We also found that this dissociation between steroid receptor expression and cell proliferation in normal epithelium was disrupted at an early stage in breast tumor formation. Recent findings presented herein support the proposal that some ERalpha/PR-positive epithelial cells are quiescent breast stem cells that act as 'steroid hormone sensors'. Such hormone sensor cells are likely to secrete positive or negative paracrine/juxtacrine factors dependent on the prevailing estrogen or progesterone concentration to influence the proliferative activity of adjacent ERalpha/PR-negative epithelial cells.