Breast cancer is becoming increasingly treatable. Yet little is known why some cells from the original tumor can hide in dormancy, and even less is known about what causes them to suddenly wake up. A new study from the laboratory of Prof. Yosef Yarden at the Weizmann Institute of Science reveals the mechanism that puts breast cancer cells to sleep, as well as the reason they emerge from dormancy more aggressive than they were before they became dormant.
Throughout their life, breast tissue cells metamorphose – from early development, when the cells are highly mobile and dividing rapidly, to the more mature, epithelial stage, when they are less active and dividing slowly. Sometimes, however, the cells go out of control and become malignant, reverting mature cells to their developmental stage, dividing rapidly, and creating tumor tissue. The cancer can also benefit from the opposite process, slowing once the cells have spread throughout the body and becoming dormant.
Scientists in Yarden’s lab in Weizmann’s Immunology and Regenerative Biology Department postulated that they might be able to induce dormancy in breast cancer cells. Using a three-dimensional model of a cancerous tumor environment, the researchers genetically modified aggressive human breast cancer cells to produce higher levels of OVOL proteins, known to be involved in the maturation of epithelial cells. The model showed that increasing the expression of two OVOL proteins halts the lifecycle of aggressive cancer cells and induces dormancy.
While this might sound like good news, it’s known that cancer patients’ breast tissue contains elevated levels of one such protein, OVOL1. The scientists hypothesized that while OVOL1 slows cancer, it also enables the cells to enter dormancy for years. When the level of OVOL1 drops, the cancer can then come back more aggressive than before.
To uncover why breast cancer tends to awaken with heightened aggression, the researchers traced the molecular signaling pathway through which OVOL1 induces dormancy. They discovered that this pathway triggers an accumulation of free radicals, unstable molecules that lead to widespread cellular damage, cell cycle arrest, and dormancy. Working with Prof. Emeritus Yosef Shiloh of Tel Aviv University, researchers showed that the accumulation of free radicals damages the dormant cells’ genetic material. This damage could explain why, upon waking up, the cancer cells are more aggressive and resistant to treatment.
“This discovery is consistent with the analysis of tissue samples from aggressive breast cancer tumors. Importantly, breast cancer is not the only malignancy that enters a state of dormancy, so understanding the mechanisms of dormancy could lead to new treatments for various other types of cancer, as well,” Yarden explains.