Laminin, long thought to be only a structural support protein in the microenvironment of breast and other epithelial tissue, is “famous” for its cross-like shape. However, laminin is far more than just a support player with a “pretty face.” Two studies led by one of the world’s foremost breast cancer scientists have shown how laminin plays a central role in the development of breast cancer, the second most leading cause of cancer death among women in the United States. In one study it was shown how laminin influences the genetic information inside a cell’s nucleus. In the other study it was shown how destruction of laminin can play a detrimental role in the early stages of tumor development.

Mina Bissell holds the title of “Distinguished Scientist” with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab). She herself is famous for having discovered the critical role in breast cancer development played by the extracellular matrix (ECM), the network of fibrous and globular proteins surrounding a breast cell. Her “dynamic reciprocity” theory holds that the fate of cells – whether they stay healthy or become cancerous – hinges on the chemical signals exchanged between the ECM and a cell’s nucleus.

In these latest studies, Bissell and her collaborators focused on laminin and its connections with two other proteins – actin, a cytoplasmic protein that has been linked to nuclear activities; and MMP9, an enzyme that is secreted outside the cells and is known to break down ECM constituents.

Laminin and Cell Quiescence

“Quiescence” is the process by which a biological cell stops growing or dividing. This is the opposite of a cancerous state, in which cell growth and division is often unchecked. Signals from laminin-111, an ECM protein that helps the cell and its ECM stick together, have been linked to cell quiescence but the mechanism was unknown. Bissell and postdoctoral fellow, Virginia Spencer, in Berkeley Lab’s Life Sciences Division, have now shown that the addition of laminin-111 leads to quiescence in breast epithelial cells through changes in nuclear actin.

“We found that high levels of laminin-111 depleted nuclear actin and this in turn induced cell quiescence,” Bissell says. “Furthermore, this process can be prevented if a form of actin that can not exit the nucleus is introduced. Under these conditions the cells do not stop growing even in the presence of laminin.”

In their study, Bissell and Spencer and their colleagues used a unique three-dimensional cell culture assay developed by Bissell’s research group, and worked with mouse and human mammary epithelial cells. Through the addition of laminin-111, they were able to decrease nuclear actin levels in the cultured cells, which reduced DNA synthesis and transcription. When nuclear actin levels were deliberately over-expressed, the effects were reversed and cells were prevented from becoming quiescent even in the presence of laminin-111. Furthermore, the high levels of nuclear actin were concentrated in regions of the breast cells where there was little or no laminin-111. Taken together, the results implicate laminin-111 as the regulator of nuclear actin and nuclear actin as a key mediator of epithelial cell quiescence.

“In collaboration with Ole Petersen’s laboratory, we had found previously that the ECM surrounding tissues from breast cancers has a dramatic reduction in laminin-111 in comparison to the ECM surrounding a normal breast cell, which is rich in laminin-111,” Bissell says. “However, just giving laminin back to cancer cells was not enough to make them normal so other factors are clearly also involved and one such factor we now know is how laminin-111 and nuclear actin talk to each other!”

Says Spencer, “Ours is the first study to actually identify laminin-111 as the physiological regulator of nuclear actin and to implicate the loss of nuclear actin as a key step in reaching quiescence and homeostasis in the mammary gland in vivo and in culture.”

Spencer believes that the interaction between laminin-111 and nuclear actin could provide a new target for diagnostic therapeutic efforts, but this will require further study.

“While it remains to be determined whether dysregulation of the levels or organization of nuclear actin is responsible for the inability of malignant cells to respond to growth-inhibitory signals from laminin-111, our preliminary results point in this direction,” she says. “In addition, the findings that laminin-111 expression is lost in myoepithelial cells isolated from human tumors should place the interaction of laminin-111 and breast tumor cells at the forefront of future investigations.”

A paper detailing the results of this study appears in the Journal of Cell Science. The paper is titled “Depletion of nuclear actin is a key mediator of quiescence in epithelial cells.” Co-authoring the paper with Bissell and Spencer were Sylvain Costes, Jamie Inman, Ren Xu, James Chen and Michael Hendzel.