Increased stem cell self-renewal and subsequent mammary stem cell enrichment are the culprits of breast cancer that develops later in life among women who were exposed to ionizing radiation as young women and girls under the age of 20 years, according to a new study. Early radiation exposure is known to substantially increase the risk for developing breast cancer later in life.

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, in which the cells do not have the estrogen receptor. Estrogen receptors are proteins that are activated by the hormone estrogen, and they are critical to the normal development of the breast and other female sexual characteristics 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 Sylvain Costes, PhD, a biophysicist with Berkeley Lab’s Life Sciences Division in California. “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.”

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The research team investigated the “window of susceptibility” that is known to exist between radiation treatments at puberty and breast cancer risk in later adulthood. The keys 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 entities 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.

Epidemiological studies have shown that girls under 20 given radiotherapy treatment for disorders such as Hodgkin’s lymphoma run about the same risk of developing breast cancer in their 40s as women who were born with a BRCA gene mutation. From their study, which was published in Stem Cells (2013; doi: 10.1002/stem.1533), the scientists concluded that self-renewal of stem cells was the most likely responsible mechanism.

“Essentially, exposure of the breast to ionizing radiation generates an overall biochemical signal that tells the system something bad happened,” 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.”