Ovarian steroids and the human breast: regulation of stem cells and cell proliferation.

Ovarian steroidal control of mammary gland proliferation and differentiation is not well defined in the human. We therefore developed the athymic nude mouse model in which intact normal human breast tissue is xenografted subcutaneously and treated with human physiological serum levels of oestrogen (E) and/or progesterone (P). We showed that: (i) E, and not P, is the major steroid hormone inducing proliferation of epithelial cells in the adult non-pregnant, non-lactating breast; (ii) E induces progesterone receptor (PR) expression; and (iii) PR expression is maximally induced at low E concentrations while a higher amount of E was required to induce proliferation. Using double label immuno-fluorescence, we demonstrated that cells expressing the oestrogen receptor-alpha (ER alpha) invariably contained the PR but that steroid receptor expression and cell proliferation (Ki67 antigen) were dissociated. Recently, we have demonstrated that some ER alpha/PR-positive epithelial cells are quiescent breast stem cells suggesting that they act as "steroid hormone sensors" that secrete paracrine factors to regulate the proliferative activity of adjacent ER alpha/PR-negative epithelial cells. The dissociation between steroid receptor expression and cell proliferation in normal epithelium was lost at an early stage in ER alpha/PR-positive breast tumour formation perhaps indicating that they arise from deregulation of the normally quiescent breast stem cells.