Understanding the Dormancy and Reactivation of Breast Cancer Cells

Breast cancer has become increasingly manageable, yet in some situations, the disease can resurface decades after patients are considered cancer-free. This resurgence is often attributed to cancer cells that detach from the primary tumor and enter a dormant state in the breast or other organs.

Current understanding of the mechanisms behind this dormancy is limited, as is the knowledge of what triggers these cells to reactivate. A recent study from the Weizmann Institute of Science unveils the process that allows breast cancer cells to enter dormancy and the reasons why they may later emerge in a more aggressive form.

The transformation of breast tissue occurs throughout a woman's life, influenced by factors such as embryonic development, puberty, pregnancy, and lactation. This process involves a shift from mesenchymal cells, which are round and highly mobile, to mature epithelial cells that are cuboidal and less active. While this process is typically regulated, it can become dysregulated, resulting in rapid cell division and malignant growth.

Interestingly, cancer cells can reverse this progression; those that have spread may revert to a more mature, dormant state, characterized by reduced mobility and slow division. Researchers at Weizmann Institute explored whether they could induce dormancy in breast cancer cells by mimicking this natural maturation process.

Utilizing a three-dimensional model of a tumor environment, the scientists modified aggressive triple-negative breast cancer cells to produce higher levels of OVOL proteins, which play a role in the maturation of epithelial cells. Their findings indicated that increased OVOL expression could halt the lifecycle of these aggressive cells and induce dormancy. In animal models, this overexpression successfully inhibited tumor growth.

However, while these results appear promising, it is important to note that elevated levels of OVOL proteins are found in the breast tissue of many cancer patients. This leads to the hypothesis that OVOL1, while it may slow cancer progression temporarily, ultimately enables cancer cells to enter a dormant state, allowing them to evade detection for years. When conditions shift and OVOL1 levels decrease, these cells can reactivate in a more aggressive form.

Researchers also investigated how cancer influences OVOL protein expression, noting that certain growth factors can enhance OVOL1 levels, while the hormone estrogen can suppress it. Observations indicated that patients with lower estrogen receptor levels and higher OVOL1 levels tend to exhibit more aggressive cancer and poorer survival rates.

Additionally, it remains unclear why reactivated breast cancer is often more aggressive. The research team traced the molecular pathways through which OVOL1 induces dormancy and discovered that this process leads to an accumulation of unstable molecules known as free radicals. These radicals cause extensive cellular damage, resulting in cell cycle arrest and dormancy.

Moreover, the researchers found that the stress endured by dormant cells due to free radical accumulation alters protein expression and function within the cell nucleus, compromising genetic material integrity and DNA repair mechanisms. This damage likely accounts for the mutations present in cancer cells upon awakening, contributing to their increased aggressiveness and treatment resistance.

Contrary to the common belief that dormant cancer cells exist in a state of suspension, this research demonstrates that these cells accumulate DNA mutations during dormancy. This significant finding has implications beyond breast cancer, as other malignancies also exhibit dormancy, suggesting that insights into dormancy mechanisms could inform treatment strategies for various cancer types.