The story of steroid hormone receptors : polymorphisms and endocrine responsiveness

Sex-hormone receptors are transcription factors involved in the physiological regulation of the reproductive function where it may promote tumorigenesis. In reproductive tissues, the physiological activity of estrogen receptor alpha (ERα) is regulated by a mechanism linking its expression with the phases of the female cycle. Receptor expression is maximal at the proliferative phase in uterus and mammary glands and is promptly downregulated in the other phases. On target cells, hormone-activated ERα induces proliferation by modulating the transcription of genes encoding key proteins for cell division (c-myc, c-fos, cyclin D1, D3, E1, E2, and B2) thus accelerating the progression through the G1 restriction point into the S phase of the cell cycle. Notwithstanding the importance of the modulation of ERα expression on target tissues, the molecular mechanism underlying this control is poorly understood. Here we demonstrate that in breast and endometrial cancer cells the ERα content during the cell cycle is regulated by a mechanism switching off the rate of RNA pol II elongation through a block to transcription mapping within intron 1. The DNA cis-acting sequence involved in this regulation is polymorphic in humans and is associated to increased risk of mammary and endometrial cancer. In addition, these polymorphisms are also associated to pathologies of the skeletal, cardiovascular and nervous systems. This study reveals a novel mechanism for the regulation of ERα activity and sets a rationale to understand the control of cell proliferation by this receptor; in addition, our data provides a mechanistic explanation for the association of PvuII and XbaI ERα polymorphysms to disease. Acknowledgments: this work was supported by the Italian Association for Cancer Research (AIRC) and by the European Community (Networks of Excellence EMIL, LSH-CT 2004–503569 and DIMI LSHB-CT-2005–512146)