Seminar

Chromatin dynamics during hormone-dependent gene regulation in breast cancer cells

Guillermo Pablo Vicent, PhD

Eukaryotic cells decode environmental information via receptors and signalling networks that converge in the cell nucleus to adjust an integrated response in form of a coordinated pattern of gene expression and transcript processing. We use the response of breast cancer cells to steroid hormones in our attempt to decipher the underlying molecular mechanisms. Eukaryotic gene regulation is associated with changes in chromatin compaction that modulate access to DNA regulatory sequences relevant for transcriptional activation or repression. Although much is known about the mechanism of chromatin remodeling in the context of hormonal gene activation, how active repression is accomplished in the chromatin context is much less understood. Our results show that 1) hormone-induced repression is characterized by a distinct sequence of complex molecular events and therefore is neither a default state nor a secondary effect of other effects of the hormone, and 2) a single ATPase of a chromatin remodeling complex also involved in transcriptional activation is sufficient for active repression, and we provide a detailed mechanism for how this can occur from the first minutes of hormone treatment. In addition, regulation of transcription in eukaryotes is dependent on the ability of combinations of transcription factors (TFs) and chromatin remodeling enzymes to modify the chromatin structure, in a manner that facilitates the coordinated expression of specific gene networks. However, little is known about the global chromatin-mediated cooperation between TFs in mammalian tissues. We have investigated the relationship between the progesterone receptor (PR) and the TF C/EBP? in breast cancer cells. Our results demonstrate that PR and C/EBP? cooperate to augment a gene expression program that enables controlled cell growth in the presence of hormone. Therapeutic strategies aimed at stabilizing C/EBP? could be viable targets for breast cancer management. Finally, our progress in the identification and characterization of high affinity PR binding sites and their putative role in breast cancer cell identity will be discussed.