Researchers at Lawrence Berkeley National Laboratory have identified the process behind how radiotherapy can increase the risk of prepubescent females developing breast cancer decades later.
The exposure to radiation in the mammary glands during puberty enriches mammary stem cells, ultimately increasing the probability of developing tumors that lack estrogen receptors. These tumors, also known as estrogen-receptor negative tumors, are typically aggressive and have a poor prognosis compared to the other breast cancer subtypes.
“What our study did was to provide a biological mechanism for this observation and also explain why ER-negative cancer is more prevalent in young women,” said Mary Helen Barcellos-Hoff, corresponding author of the paper and a professor in the departments of radiation oncology and cell biology at New York University.
The researchers used an original integrative approach incorporating multiscale computer models, in vitro experiments with human breast cell lines and other techniques.
According to Barcellos-Hoff, this is the first multiscale model created for mammary glands to simulate their growth from puberty to adulthood. This method simulated the effects of ionizing radiation on the mammary gland at various stages of development.
“We ran thousands of simulations of our model on the Lawrencium supercomputer in order to validate the model,” said Jonathan Tang, lead author of the paper and a postdoctoral student at UC Berkeley, in an email. “The multi-scale computer models played an essential role in linking the data across all of the experiments to identify the most likely mechanism.”
The research results indicated radiation induces certain proteins and transforms the regulation of certain cellular processes. These two factors cooperate to stimulate stem-cell self-renewal, the molecular mechanism behind the increase in mammary gland stem cells resulting from ionizing radiation. The researchers showed the mechanism is effective only when there is active proliferation, such as during puberty, when the mammary gland is developing.
“By understanding the mechanism at some point down the line, we will be able to protect people who are treated with radiation,” Barcellos-Hoff said. “One would hope we will be able to intervene and treat that.”
Radiotherapy is used to treat cancer, but using this treatment on young girls increases their risk of developing a second cancer in later years, according to Barcellos-Hoff.
Sylvain Costes, a co-corresponding author on the study and a biophysicist at the Berkeley lab, said previous studies showed that ionizing radiation causes cancer only by inducing DNA damage and gene mutations. Costes noted, however, that other factors may be at play.
He said increased stem cell frequency at doses of ionizing radiation similar to those received from head and cardiac X-ray computed tomography may trigger the development of aggressive tumors.
In an effort to continue their research, Costes and Tang have co-founded a startup, Exogen Biotechnology Inc., that strives to use biomarkers to identify young girls who are at risk of developing cancer after exposure to ionizing radiation therapy.
Mark Tan covers research and ideas. Contact him at [email protected].
A previous version of this article may have implied that radiotherapy increases the risk of prepubescent females developing breast cancer. It increases the risk of prepubescent females developing breast cancer decades later.
A previous version of this article may have also implied that x-ray and CT scan procedures can trigger the development of aggressive tumors. It is the increased stem cell frequency at doses of ionizing radiation that may be given during these procedures that may do so.
A previous version of this article incorrectly stated that the researchers’ model worked by monitoring different characteristics of the mammary gland at various stages of development. In fact, the model simulated the effects of ionizing radiation on the mammary gland at various stages of development.
A previous version of this article also incorrectly stated that estrogen-receptor negative tumors impede the healthy development of the female body. In fact, these tumors are typically aggressive and have a poor prognosis compared to the other breast cancer subtypes, according to the research.