February 20, 2014

Studies shed new light on breast cancer development

Rebecca Cook, Ph.D., assistant professor of Cancer Biology, has spent her life trying to understand what makes things grow, from seedlings in soil to tumor cells in the body.

Rebecca Cook, Ph.D., has two recent papers exploring how developmental events in the breast affect formation and progression of breast cancer. (photo by Steve Green)

Rebecca Cook, Ph.D., assistant professor of Cancer Biology, has spent her life trying to understand what makes things grow, from seedlings in soil to tumor cells in the body.

That interest has led to her growing reputation for scientific publications in the field of breast cancer, including two recent papers on how normal developmental events in the breast affect the formation and progression of breast cancers.

Growing up in rural Alaska helped nurture Cook’s love of science.

“From the time I was little I was interested in how the cycles of nature worked,” said Cook.
That interest led to an undergraduate biology degree from Vanderbilt, followed by a Ph.D. in developmental biology from the University of Cincinnati and more postdoctoral training at Vanderbilt under Carlos Arteaga, M.D., director of the Center for Cancer Targeted Therapies and director of the Breast Cancer Program.

After a research stint at the University of North Carolina, Cook returned to Vanderbilt in 2008. Several breast cancer research papers soon helped Cook garner funding from the National Cancer Institute, Susan G. Komen for the Cure and the Department of Defense. Today, her Vanderbilt research laboratory focuses on increasingly complex questions about molecular events in normal breast cells, and how this contributes to cancer.

“The breast is fascinating to study from a developmental perspective. While most organs develop during gestation and childhood, the breast develops primarily during puberty and adulthood,” Cook explained.

Many cells in the breast (the ductal cells) are established during puberty, and others (the milk-producing cells) during pregnancy, said Cook. Once nursing ends, those milk-producing cells die, and the breast undergoes a dramatic remodeling process called post-partum involution. A final remodeling event occurs during menopause, eliminating much of the remaining breast cells, in a process termed lobular involution, a process that Cook says is “fascinating, poorly understood, but clinically relevant,” as incomplete lobular involution correlates with an increased incidence of breast cancer.

Deciphering what regulates these developmental changes is crucial for scientists studying breast cancer.

“Each developmental phase in the breast opens a unique window of opportunity for breast cells to acquire alterations that may increase breast cancer susceptibility, and engages remodeling events in the breast environment that enhance tumor progression,” Cook said.

Her research in this arena captured the attention of the Journal of Clinical Investigation, which published two studies from Cook in recent months.

One paper, for which Cook served as lead author, studied MerTK, a protein active in the immune system in a cell called a macrophage. These cells invade and remodel the breast during involution. Tumor-associated macrophages (TAMs) contribute to malignant tumor progression, in part by suppressing the body’s immune response against tumors.

Cook and colleagues found that MerTK inhibition prevented TAMs from suppressing the body’s anti-tumor immune response. Instead, MerTK-deficient macrophages directed T-lymphocytes to attack the tumor, decreasing tumor growth and metastasis.

“This implies tumor macrophages suppress tumor immunity in large part through MerTK,” explained Cook. New MerTK drugs in preclinical development might be combined with current treatments to increase tumor cell death.

As senior author of another study, Cook found that luminal (estrogen-responsive) breast cancers rely heavily on ErbB3, a protein often overlooked. Cook previously discovered that ErbB3 drives breast cell survival during puberty. Cook similarly found that breast tumor cells rely on ErbB3 for survival, especially when treated with anti-estrogen drugs like fulvestrant. Antibodies targeting ErbB3 improved tumor cell killing in combination with fulvestrant.

Both recent studies demonstrate how Cook uses an understanding of normal breast development to improve breast cancer treatments for patients.