Image: Computation model of the developing mammary gland beginning at three weeks of age (Photo courtesy of the US Department of Energy’s Lawrence Berkeley National Lab’s Life Sciences Division
Exposing young women and girls under the age of 20 to ionizing radiation can substantially raise the risk of their developing breast cancer later in life. Scientists may now have found the answer as to why this occurs. A collaborative study’s findings pointed to increased stem cell self-renewal and consequential mammary stem cell enrichment as the reason.
Breasts enriched with mammary stem cells as a result of ionizing irradiation during puberty show a later-in-life propensity for developing estrogen receptor (ER)-negative tumors. Estrogen receptors, i.e., proteins activated by the estrogen hormone, are vital for the normal development of the breast and other female sexual features during puberty.
“Our results are in agreement with epidemiology studies showing that radiation-induced human breast cancers are more likely to be ER-negative than are spontaneous breast cancers,” said Dr. Sylvain Costes, a biophysicist with US Department of Energy’s (DOE) Lawrence Berkeley National Lab’s Life Sciences Division (LBL; Berkeley, CA, USA). “This is important because ER-negative breast cancers are less differentiated, more aggressive, and often have a poor prognosis compared to the other breast cancer subtypes.”
Drs. Costes and Jonathan Tang, also with Berkeley Lab’s Life Sciences Division, were part of a collaboration led by Dr. Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine (New York, NY, USA), that studied the so-called “window of susceptibility” known to exist between radiation treatments at puberty and breast cancer risk in later adulthood. The key to their success were two mammary lineage agent-based models (ABMs) they developed in which a system is modeled as a collection of autonomous decision-making units called agents. One ABM simulated the effects of radiation on the mammary gland during either the developmental stages or during adulthood. The other simulated the growth dynamics of human mammary epithelial cells in culture after irradiation.
“Our mammary gland ABM consisted of millions of agents, with each agent representing either a mammary stem cell, a progenitor cell or a differentiated cell in the breast,” stated Dr. Tang. “We ran thousands of simulations on Berkeley Lab’s Lawrencium supercomputer during which each agent continually assessed its situation and made decisions on the basis of a set of rules that correspond to known or hypothesized biological properties of mammary cells. The advantage of this approach is that it allows us to view the global consequences to the system that emerge over time from our assumptions about the individual agents. To our knowledge, our mammary gland model is the first multiscale model of the development of full glands starting from the onset of puberty all the way to adulthood.”
Epidemiologic research have shown that girls under 20 administered radiotherapy treatment for disorders such as Hodgkin’s lymphoma have about the same risk of developing breast cancer in their 40s as women who were born with a BRCA gene mutation. From their study, Drs. Costes, Tang, and their colleagues concluded that self-renewal of stem cells was the most likely responsible process.
“Stem cell self-renewal was the only mechanism in the mammary gland model that led to predictions that were consistent with data from both our in vivo mouse work and our in vitro experiments with MCF10A, a human mammary epithelial cell line,” Dr. Tang noted. “Additionally, our model predicts that this mechanism would only generate more stem cells during puberty while the gland is developing and considerable cell proliferation is taking place.”
The investigators are now looking for genetic or phenotypic biomarkers that would identify young girls who are at the greatest breast cancer risk from radiotherapy. The study’s findings from Dr. Barcellos-Hoff and her research group show that the ties between ionizing radiation and breast cancer extend beyond DNA damage and mutations.
“Essentially, exposure of the breast to ionizing radiation generates an overall biochemical signal that tells the system something bad happened,” Dr. Costes said. “If exposure takes place during puberty, this signal triggers a regenerative response leading to a larger pool of stem cells, thereby increasing the chance of developing aggressive ER-negative breast cancers later in life.”
The findings of this collaborative study have been published online August 23, 2013, in the journal Stem Cells.
Lawrence Berkeley US National Lab’s Life Sciences Division