Mechanisms of resistance to hormone therapy

Abstract

We know that many human breast cancers are dependent upon the steroid hormones, estrogen and progesterone for their growth, and that their effects are mediated through the estrogen receptors (ERs a and β) and progesterone receptors (PRs A and B). Targeted therapy directed at reducing the mitogenic effects of estrogen through blockade of the ERs was the first [4], and remains the most frequently prescribed form of systemic therapy, especially for postmenopausal human breast cancer. The recent clinical success of the aromatase inhibitors (AIs) [114], and the potential for sequencing of these agents with antiestrogens [10] has further enhanced our management of the disease. But while these targeted strategies are initially useful in many breast cancer patients, acquired hormonal resistance (HR) eventually develops with the appearance of metastatic lesions in patients. An emerging hypothesis is that the ERs remain central to the problem of resistance, due to their molecular crosstalk with growth factors, or possibly other intracellular signaling molecules. Recent information concerning the molecular basis for HR and the molecular mechanisms associated with receptor function has helped elucidate potential new therapeutic strategies and treatment combinations with promise for the clinic. The aims of this chapter will be to review the role of the ER signaling network as the integral foundation for assessing clinical outcome and selecting appropriate therapies for ER-positive breast cancer. © Springer-Verlag Berlin Heidelberg 2006.