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How Does Nuclear Organization Maintain Normal Mammary Phenotype?

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Final rept. 1 Jul 2000-28 Feb 2005

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Degradation of the basement membrane BM surrounding breast epithelial units acini is associated with tumor progression. It is crucial to understand the molecular mechanisms that underlie the maintenance of an intact EM in order to develop anti-cancer strategies. Using non-neoplastic human breast epithelial S1 cells that differentiate into acini in the presence of extracellular matrix, we have shown a link between the nuclear organization of the protein NuMA and the maintenance of acinar differentiation, notably BM integrity. Sequence analysis of the distal portion of NuMA C-terminus NuMA-CTDP revealed that this region may be restricted to vertebrates and may adopt a structure possessing organizational and signaling properties. In addition, NuMA-CTDP shares similarities with sequences of proteins involved in chromatin structure. Expression of NuMA-CTDP in S1 cells altered chromatin structure and impaired acinar differentiation and formation of the EM. Cell fractionation showed that NuMA interacts with the chromatin compartment and suggested that NuMA might be associated with multi-protein complexes. NuMA has been recently identified as a possible candidate for breast cancer predisposition. By establishing a role for NuMA in chromatin organization critical for mammary epithelial differentiation, our work sheds light on how alterations in NuMA function may lead to cancer development.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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