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Radiotherapy Contributes to Risk of Breast Cancer in Girls Later in Life

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Young women and girls under the age of 20 who undergo radiotherapy can significantly raise the risk of them contracting breast cancer later in life.

In a joint study where Berkeley Lab researchers played a crucial part, alluding to increased stem cell self-renewal and consequent mammary stem cell enhancement as the reason.

Breasts enhanced with mammary stem cells due to the process of ionizing irradiation during puberty present a later-in-life tendency for developing ER negative tumors, which are cells that do not have the estrogen receptor; which are proteins enabled by the estrogen hormone that are vital 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.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,” said biophysicist with Berkeley Lab's Life Sciences Division, Sylvain Costes.

Costes and Jonathan Tang, who was also with Berkeley Lab's Life Sciences Division, were part of a collaboration headed by Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine, that explored and analyzed the so-called "window of susceptibility," a condition known to stem from the use of radiation treatments in young women during puberty which can later lead to breast cancer during adulthood.

A key component to the researcher’s success was two mammary lineage agent-based models (ABMs) they produced in which a system is modeled as a compilation of independent 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. 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 multi-scale model of the development of full glands starting from the onset of puberty all the way to adulthood,” said Tang.

Additionally, epidemiological studies have demonstrated that girls below the age of 20 who receive radiotherapy treatment for disorders such as Hodgkin's lymphoma are just as prone to developing breast cancer in their 40s as women who were born with a BRCA gene mutation.

From their study, Costes, Tang and their collaboration partners concluded that self-renewal of stem cells was the most likely responsible mechanism.

"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. 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,” said Tang.

As of now, Costes and Tang are seeking genetic or phenotypic biomarkers that would help identify young girls who are at the highest risk of developing breast cancer following radiation therapy. The results of their study with Barcellos-Hoff and her research group show that the links 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. 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,” Costes concluded.

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