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Involvement of Two Novel Morphoregulatory Molecules in Breast Morphogenesis and Invasive Cancer

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Annual rept. 6 Sep 2001-5 Sep 2002

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The hyaluronan binding protein RHAMM is located on the cell surface in the cytoplasm and the nucleus as well as lamellae and in these characteristics resembles the morphogenic branching factor epimorphin. Our goal was the identification and characterization of the interplay between RHAMM and epimorphin during mammary gland morphogenesis and, for the future, breast tumor progression. In order to begin to identify and investigate a function for RHAMM during. epimorphin-regulated mammary gland morphogenesis we analyzed RHAMM expression in virgin and pregnant mice and studied the effect of RHAMM deficiency on in vivo and in vitro branching morphogenesis. RHAMM is expressed by breast epithelial cells, as detected by RT-PCR and western blot analysis and expression increases during pregnancy as shown by RT-PCR analysis, immuno staining and in situ hybridization. Mammary glands isolated from RHAMM 4- mice show reduced secondary branching compared to mammary glands isolated from wild type wt mice. Absence of RHAMM due to genetic deletion or inhibition of RHAMM function by function blocking reagents e.g. antibodies or recombinant protein fragments, leads to enhanced branching in in vitro assays. This difference between in vivo and in vitro results suggests that the in vitro environment might provide factors e.g. growth factors, which are limiting in the in vivo environment, possibly due to the loss of the RHAMM gene. Resurfacing of scratch wounds of breast epithelial cell monolayer is enhanced in the presence of function blocking anti-RHAMM antibodies and regulation of cell motility might be one mechanism by which RHAMM influences branching morphogenesis.

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  • Biochemistry
  • Medicine and Medical Research

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