Pharmacological modulation of local feedback mechanisms as a therapeutic approach in breast cancer treatment.

ABSTRACT

Breast function and development are regulated by a network of local and systemic signals which can exert either stimulatory or inhibitory effects. Many of these signals are mediated by topically produced hormones and cytokines, which are both believed to be part of complex feedback loops. Over the last few years it has become increasingly clear that local feedback mechanisms also play an integral part in the growth and local invasion of malignant breast tumors. The intratumoral development of positive feedback loops can not only enhance the malignant phenotype and growth rate of tumor cells, but is also thought to stimulate the formation of vascular elements to ensure a sufficient supply of nutrients. In addition, the disruption of physiological negative feedback loops in breast tissue might result in the loss of cell cycle control and eventually lead to increased tumor growth and local breakdown of adjacent stroma. It is therefore not surprising that many of these loops involve interactions between tumor cells and their stromal environment, and are located at the site of tumor invasion. Since several of the potentially involved cytokines are already known and a number of specific inhibitors are now available, it is possible to interrupt pathological intercellular communication by selectively inhibiting intratumoral key feedback mechanisms. While the identification of each new intratumoral feedback loop can help us in our quest for for novel specific antineoplastic strategies, we now also know that some of the most commonly used endocrine therapies are probably so effective because they also interfere with local intercellular communication.