graphic

The movements (colored lines) of breast epithelial cells within acini can occur without invasion.

Breast cancer cells dance around the subject before becoming invasive, if results from Pearson and Hunter are any indication. The findings show that mammary epithelial cells can become motile within their environment without being invasive. Their motility, however, places them one step closer to metastasis.

Many breast cancers are hallmarked by the unchecked activity of the ERK1/2 MAP kinase pathway. Pearson and Hunter investigated the mechanism by which these kinases, which are normally activated by extracellular growth factors, lead to tumorigenesis. They imaged breast epithelial cells in a 3D model that mimics their in vivo environment. In this model, the cells polarize on a basement membrane to form hollow spheres called acini.

Within mature acini, the provoked action of ERK1/2 encouraged cells to leave their appointed locations. They glided along the basement membrane (underneath other cells) or within the lumen of the acini (on top of the other cells). Motility required the activation of a myosin motor by a kinase that is a known target of ERK1/2.

The movements resembled those that occur in developmental contexts, such as in the forming kidney or salivary gland. These programs are shut down when cells differentiate but might be wrongly reactivated in cancers.

Dangerously invasive cells are characterized by their ability to break through the basement membrane, but this escape was not seen in the ERK-activated acini. The cells did not display the usual set of molecular changes, including increases in N-cadherin and vimentin, that accompany the epithelial–mesenchymal transition. Nonetheless, the movements disrupted the architecture of the acini, as the wandering cells squeezed between more well-behaved stationary cells.

Although not yet invasive, motile breast cells might suggest that a more aggressive form of cancer is brewing. With the ability to flee already in place, these cells would require fewer mutations to become fully invasive. The authors hope to identify molecular markers of this motility that will help physicians diagnose those patients who are at a higher risk for metastases. Motile but noninvasive cells might also permeate other epithelial cancers, including lung and bladder cancers.

Reference:

Pearson, G.W., and T. Hunter.
2007
.
J. Cell Biol.
179
:
1555
–1567.