Macrophages, estrogen and the microenvironment of breast cancer

Estrogen is a major mitogenic stimulus to established breast cancer. Estrog en sources include ovarian, extraglandular sites and breast tissue. Which s ource primarily maintains benign and breast cancer tissue estrogen concentr ations remains unclear. While macrophages may comprise up to 50% of the mas s of breast carcinomas, previous studies neglected to study them as possibl e sources of estrogen. We present evidence that breast macrophages constitu te an in situ source of estradiol and that the amount produced is sufficien t to mediate cellular proliferation. We utilized immunohistochemistry and R T-PCR to study cell-specific aromatase expression in (i) 29 breast biopsies , (ii) human monocytes/macrophages and (iii) a myeloid cell, line (THP-1) c apable of differentiating into macrophages. Use of a breast cancer cell lin e (MCF-7) provided biologic confirmation of the role of aromatization in ce ll proliferation. We demonstrated considerable amounts of immunoreactive-ar omatase (irARO) in breast tissue macrophages and a positive correlation bet ween the proportion of irARO present in macrophages and lesion severity. Us ing in vitro techniques, we demonstrated that monocytes and THP-1 cells req uire differentiation into macrophages to produce aromatase in amounts appro aching placental levels. The amount of estrogen produced by THP-1 cells sti mulated MCF-7 cells to proliferate, an effect blocked by aromatase inhibito rs. Estrogen production by macrophages in breast tissue appears sufficient to stimulate the proliferation of adjacent epithelial cells and to autoregu late cytokine production. These findings represent a new dimension of cellu lar regulation in breast tissue with major biologic implications, amenable to pharmacological manipulation. (C) 1999 Elsevier Science Ltd. All rights reserved.