Should prolactin be reconsidered as a therapeutic target in human breast cancer?

Although prolactin (PRL) has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists, which lower circulating levels of PRL, rapidly reduced the interest of oncologists concerning a potential role of this pituitary hormone in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized in the mammary gland, and second that it exerts its proliferative action in an autocrine/paracrine manner. These observations have led to a reconsideration of the role of PRL as an active participant in breast cancer and are an impetus to search for alternative strategies aimed at inhibiting the proliferative effects of PRL on tumor mammary cells. In this report, we discuss the three possible levels that can be targeted for this purpose: the mammary synthesis of PRL, the interaction of the hormone with its receptor at the surface of mammary cells, and the intracellular signaling cascades triggered by the activated receptor. For each of these steps, we discuss the molecular event(s) that can be targeted, our understanding of the mechanisms involving these putative targets as well as the tools currently available for their inhibition. Besides its proliferative effect, PRL is also involved in the control of angiogenesis through one of its cleaved fragments, named PRL 16K, which has been shown to inhibit the angiogenic process. In view of this biological activity, we discuss first the cleavage of PRL with respect to the human mammary gland and, second, the hypothesis speculating that a balance between the proliferative effect of intact PRL and the anti-angiogenic activity of its 16K-like fragments might be physiologically relevant in the evolution of mammary tumors. If true, our hypothesis would suggest that the enzymatic cleavage of PRL could represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.