A paper detailing the results of this study has appeared in the journal Genes and Development. The paper is titled "Raf-induced MMP9 Disrupts Tissue Architecture of Human Breast Cells in Three-Dimensional Culture and is Necessary for Tumor Growth in vivo." Co-authoring the paper with Bissell were Alain Beliveau, Joni Mott, Alvin Lo, Emily Chen, Antonius Koller, Paul Yaswen and John Muschler.
Using a model of human breast cancer where breast epithelial cells were grown in three-dimensional cultures of basement membrane, a thin layer of ECM material that envelops breast and other glandular tissue, Bissell and her co-authors found that not only did excessive MMP9 activity disrupt tissue architecture, but that silencing MMP9 restored tissue architecture and decreased the ability of human beast cancer cells to form tumors in mice.
"We found that in all conditions where tumor cells could be reverted to a normal phenotype in our 3D assays, a novel signaling loop through a pathway of Raf/MEK/ERK proteins was responsible for MMP9 activity in the breast tumor cells," says co-author Joni Mott, a researcher with Bissell's group in Berkeley Lab's Life Sciences Division. "Once MMP9 was activated, the proteinase targeted the destruction of laminin-111 within the basement membrane."
Laminin-111 in the basement membrane, Mott explains, allows mammary epithelial cells to establish a normal polarized structural unit called an "acinus," which is responsible for storing milk and making it available for babies when they suckle.
In their Genes and Development paper, Bissell, Mott and their co-authors reported that when the integrity of the tissue architecture was compromised by laminin proteolysis, the basement membrane no longer provided the appropriate signals to restrain epithelial cell proliferation. The result was a sustained signaling of the Raf/MEK/ERK pathway that leads to continued MMP9 production
|Contact: Lynn Yarris|
DOE/Lawrence Berkeley National Laboratory