Involvement of prolactin in breast cancer: redefining the molecular targets

The mammary gland is the major target tissue of prolactin (PRL) in mammals. Although this pituitary hormone has been long suspected to be involved in the progression of human breast cancer, the failure or clinical improvement by treatment with dopamine agonists (which lower circulating levels of PRL ) rapidly reduced the interest of oncologists concerning a potential role o f PRL in the development of breast cancer. Within the last few years, howev er, several studies reported first, that PRL is also synthesized by mammary epithelial cells, and second that it may exert a proliferative action in a n autocrine/paracrine manner. Tn agreement with a recent epidemiological st udy, these observations have led to a reconsideration of the role of PRL as an active participant in breast cancer, and are an impetus to redefine the molecular targets of anti-prolactin strategies since dopamine analogs are assumed to be inefficient on extrapituitray PRL synthesis. In this review, we briefly summarize the current knowledge of PRL effects on both normal an d tumor mammary cells, and we discuss the most relevant articles supporting the autocrine-paracrine action of PRL in the breast. With the aim of defin ing putative new molecular targets, we propose an overview of the main PRL receptor signaling cascades known to be triggered by PRL in mammary epithel ial cells or, when not available, in other cell types. Finally, because pro teolytic fragments of rat PRL have been shown to inhibit the angiogenic pro cess, which may be relevant for preventing the progression of solid tumors such as breast tumors, we discuss the hypothesis that the enzymatic cleavag e of human PRL could also represent a new molecular target in the search fo r alternative strategies in the treatment of breast cancer. (C) 2000 Elsevi er Science Inc. All rights reserved.