an-ex-vivo-model-to-study-hormone-action-in-the-human-breast

An <em>Ex vivo</em> Model to Study Hormone Action in the Human Breast

The study of hormone action in the human breast has been hampered by lack of adequate model systems. Upon in vitro culture, primary mammary epithelial ...

Ecole Polytechnique Fédérale de Lausanne

The oncoprotein SET/TAF-Ibeta is a histone chaperone which is involved in cell-cycle control and chromatin remodeling. Confocal laser scanning microscopy reveals that SET is localized in distinct foci of variable size throughout the nucleoplasm of interphase cells. We report here that SET interacts directly with the acetyltransferase CREB-binding protein (CBP) and enhances the transactivation potential of the transcription coactivator. Our data suggest that the histone chaperone SET regulates the CBP-mediated transcription and may indicate a general principle by which transcriptional regulators cooperate with histone chaperones for gene activation.

The histone chaperone SET/TAF-Ibeta interacts functionally with the CREB-binding protein.

SARA, an early endosomal protein, plays a key role in TGFβ signalling, as it presents SMAD2 and SMAD3 for phosphorylation by the activated TGFβ receptors. Here, we show that ERBIN is a new SARA-interacting protein that can be recruited by SARA to early endosomes. ERBIN was recently shown to bind and segregate phosphorylated SMAD2 and SMAD3 (SMAD2/3) in the cytoplasm, thereby inhibiting SMAD2/3-dependent transcription. SARA binds to ERBIN using a new domain, which we have called the ERBID (ERBIN-binding domain), whereas ERBIN binds to SARA using a domain (amino acids 1208-1265) that also interacts with SMAD2 and SMAD3, which we have called the SSID (SARA- and SMAD-interacting domain). We additionally show that SARA competes with SMAD2/3 for binding to ERBIN. In agreement, overexpression of SARA or the ERBID peptide reverses the inhibitory effect of ERBIN on SMAD2/3-dependent transcription. Taken together, these data suggest that the response of cells to TGFβ and activin A can be influenced by the relative concentrations of SARA, ERBIN and SMAD2/3.

ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN.

Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.

Article	Year
The histone chaperone SET/TAF-Ibeta interacts functionally with the CREB-binding protein. Biochemical and biophysical research communications\| PubMed ID: 16061203	2005
ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN. Journal of cell science\| PubMed ID: 21878490	2011
Progesterone/RANKL is a major regulatory axis in the human breast. Science translational medicine\| PubMed ID: 23616122	2013
A new Achilles Heel in breast cancer? Oncotarget\| PubMed ID: 23907591	2013

George Sflomos

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