Post-pregnancy events promote breast tumor metastasis

Changes in the tissue environment of the breast that occur after pregnancy promote the metastasis of breast tumor cells. The paper by McDaniel et al., “Remodeling of the mammary microenvironment following lactation promotes breast tumor cell metastasis,” appears in the February issue of The American Journal of Pathology and is accompanied by a commentary.

This work also highlights an important shift in thinking about what influences cancers to metastasize: the move from studying specific gene mutations to studying the tumor environment. The focus on the tumor environment, or stroma, has been gaining strength in recent years, as detailed in the commentary by Sonnenschein and Soto.

The human breast undergoes dramatic changes during the course of pregnancy, lactation, and involution (the process by which the milk-producing tissue is reabsorbed and the breast returns to “normal”). These processes require mammary cells to proliferate, differentiate, and finally die, events that are partly driven by changes in the environment surrounding the cells, or extracellular matrix. How these changes affect the outcome of breast cancer is of great interest, especially considering the epidemiological link between breast cancer after pregnancy and poor prognosis.

Under the leadership of Dr. Pepper Schedin, researchers at the AMC Cancer Research Center of University of Colorado Health Science Center compared extracellular matrix from mammary glands of rats exhibiting post-lactation involution to that of virgin rats. They found that the involution matrix contained higher levels of matrix proteases and degraded proteins and generally more matrix proteins than virgin matrix, indicating that involution matrix was undergoing significant structural changes. When immortalized “normal” human breast cells were grown on each type of matrix, only virgin matrix supported formation of mammary duct-like structures, further demonstrating signaling differences inherent to the source of matrix.

In vitro invasion assays established that human breast tumor cells migrated much better through the involution matrix than through virgin matrix. Schedin’s group next performed in vivo experiments to further confirm that post-lactation involution matrix enhances tumor cell migration (i.e. metastasis). Breast tumor cells were mixed with either involution or virgin matrix, and the mixtures were injected into the mammary fat pads of mice. Human tumor cells formed small mammary tumors, regardless of matrix source; however, the involution matrix exerted a more powerful push toward metastasis, with cells spreading to the lung, liver and kidney, expressing higher levels of the human vascular growth factor VEGF and increasing blood vessel development.

These data demonstrate the importance of the changing breast environment in the evolution of breast cancer. Specifically, changes in the extracellular matrix that occur during post-pregnancy involution may actually promote metastasis of breast cancer following pregnancy. The authors further offer that these data may explain why women with breast cancer diagnosed up to 5 years after pregnancy are at greater risk of developing metastases.