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Vanderbilt-led study investigates potential postpartum breast cancer therapy

Nearly 25 percent of all breast cancers among premenopausal women occur within two to five years following a pregnancy. These postpartum tumors are more likely to spread or metastasize to other parts of the body, leading to an increased risk of death.

“Unfortunately, these are young women who have just had children. All deaths are tragic but the loss of a young woman who is also a mother is so devastating for families and has a profoundly negative societal impact,” said , Ph.D., assistant professor of Cancer Biology at , Nashville, Tennessee.

A new study led by Cook and published in the Journal of Clinical Investigation helps explain the cellular activity that leads to breast tumor metastasis among women who have recently given birth. Other contributors include first author , Ph.D., a former VICC postdoctoral fellow now working for the , and collaborators at the University of North Carolina and the University of Illinois.

Breast tissues undergo massive transformations during pregnancy in preparation for nursing the new infant. After milk production has ended, there is a cascade of cell death.

“This cell death removes about 90 percent of breast epithelial cells during a very short window of time, which triggers widespread remodeling and repair of by the immune system,” explained Cook.

During this remodeling, immune cells called macrophages operate like tiny Pac-Man arcade game characters, gobbling up the dying cells before the dying cells can release intracellular contents which can provoke immune attack. As another safeguard against immune attack, macrophages that ‘eat’ dying cells also secrete immune suppressive factors. Macrophages use one molecule – MerTK – to control both of those processes.

Using a mouse model, Cook and her colleagues found that immune suppression in the postpartum breast triggered by MerTK mistakenly protects tumors, increasing their ability to spread.

“This is similar to an amplified wound healing response that is orchestrated and amplified by MerTK, and that drives tumor malignancy,” said Cook.

The investigators treated mice harboring postpartum tumors with an investigational drug labelled BMS-777607, designed to inhibit the Mer tyrosine kinase (MerTK). Following treatment, investigators saw decreased clean-up of dying breast cells in the postpartum breast, decreased immune suppression and decreased metastasis. The drug, which is in clinical testing for other forms of cancer, was used for just seven days to avoid disrupting the immune response and creating autoimmunity.

While more research is needed, Cook said the results suggest that using a MerTK inhibitor in conjunction with other therapies could be helpful.

“MerTK-directed therapies may prevent the accelerated rate of tumor spread caused by the postpartum remodeling processes. This would be a short window of treatment in the postpartum period but with the long-term benefit of preventing tumor recurrence at distant sites,” said Cook.

In the meantime, Cook said women who have recently given birth need to be vigilant about breast health.

Other investigators who contributed to the study include Christian Young, Ph.D., Donna Hicks, Philip Owens, Ph.D., Andrew Williams, David Vaught, Ph.D., Meghan Morrison, Jiyeon Lim, Michelle Williams, Dana Brantley-Sieders, Ph.D., Justin Balko, Pharm.D., Ph.D., Vanderbilt; Debra Tonetti, M.D., University of Illinois; and H. Shelton Earp III, M.D., University of North Carolina.

Funding for the study was provided by the National Cancer Institute, a division of the National Institutes of Health, (CA143126, CA009592), the Department of Defense (BC120793), and the Susan G. Komen Foundation.

Source

Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution, Jamie C. Stanford, Christian Young, Donna Hicks, Philip Owens, Andrew Williams, David B. Vaught, Meghan M. Morrison, Jiyeon Lim, Michelle Williams, Dana M. Brantley-Sieders, Justin M. Balko, Debra Tonetti, H. Shelton Earp, III and Rebecca S. Cook, Journal of Clinical Investigation, doi:10.1172/JCI76375, published 24 September 2014.

Source: Vanderbilt-Ingram Cancer Center