Molecular Cause of Breast Cancer Metastasis Discovered

By Jeffrey Perkel
HealthDay Reporter
Friday, April 4, 2008; 4:00 AM

Copyright © 2008 ScoutNews, LLC. All rights reserved.

THURSDAY, April 3 (HealthDay News) -- Certain cancers tend to spread to specific tissues, and now researchers have gained a molecular handle on how that happens.

Working with breast tumors, Joan Massague, chairman of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York City, and his colleagues discovered a signaling "relay" that enables the cancer to molecularly "soften" its target tissue -- the lung in this case -- allowing circulating breast cancer cells to pass through capillary walls and penetrate the lung.

"It provides a very nice mechanism for how breast cancer cells specifically get out of the circulation and into the lungs. Nobody knew how they did that before," said Karl Saxe, a scientific program director at the American Cancer Society.

The results were published in the April 4 issue of Cell.

Key to this study is a signaling molecule called TGF-beta. Early in cancer progression, TGF-beta acts as a tumor suppressor, inhibiting cancer growth. Later, it actually stimulates cancer progression and metastasis. Massague was interested in how tumors trigger this molecular dichotomy.

His team began by identifying a molecular signature, a pattern of gene expression of 153 genes that identifies tumors that are both expressing and responding to TGF-beta. They then applied that signature to hundreds of primary breast tumors.

While there was no apparent correlation between TGF-beta signaling and metastasis in breast cancers that also express the estrogen receptor, the team found that tumors that were estrogen receptor-negative and signature-positive were much more likely to metastasize to lung. No similar correlation was found for metastasis to the bone, liver or brain.

When the team then asked which of the genes in the signature was responsible for this selectivity, they identified a second element in the relay, a signaling molecule called angiopoietin-like 4 (ANGPTL4), whose expression is induced by TGF-beta. ANGPTL4 disrupts capillary walls, loosening the connections between adjacent cells and allowing the metastasizing cells to "seed" the tissue.