Radiotherapy in girls and the risk of breast cancer later in life

September 11, 2013 by Lynn Yarris
This mammary gland agent-based model depicts the network structure at week three formed by cell agents that come together to form duct agents. In turn, duct agents organize into a network similar to the branched structure of the mammary gland. Credit: Jonathan Tang, Berkeley Lab

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 know why. A collaborative study, in which Berkeley Lab researchers played a pivotal role, points to increased stem cell self-renewal and subsequent mammary stem cell enrichment as the culprits. Breasts enriched with mammary stem cells as a result of ionizing irradiation during puberty show a later-in-life propensity for developing ER negative tumors - cells that do not have the estrogen receptor. Estrogen receptors - proteins activated by the estrogen hormone - 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," says Sylvain Costes, a biophysicist with Lawrence Berkeley National Laboratory (Berkeley Lab). "This is important because ER negative breast cancers are less differentiated, more aggressive, and often have a compared to the other subtypes."

Costes and Jonathan Tang, also with Berkeley Lab, were part of a collaboration led by Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine, that investigated the so-called "window of susceptibility" known to exist between radiation treatments at puberty and 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 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.

"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," says 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 multi-scale model of the development of full glands starting from the onset of puberty all the way to adulthood."

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

Jonathan Tang (left) and Sylvain Costes developed an agent-based model that is the first multi-scale model of the development of a mammary gland from the onset of puberty all the way to adulthood. Credit: Roy Kaltschmidt, Berkeley Lab

"Stem cell self-renewal was the only mechanism in the 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," Tang says. "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."

Costes and Tang are now looking for genetic or phenotypic biomarkers that would identify young girls who are at the greatest breast cancer risk from 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 generates an overall biochemical signal that tells the system something bad happened," Costes says. "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."

Explore further: Predicting individual breast cancer risk may be possible

Related Stories

Predicting individual breast cancer risk may be possible

August 12, 2013
An international scientific collaborative led by the Harvard Stem Cell Institute's Kornelia Polyak, MD, PhD, has discovered why women who give birth in their early twenties are less likely to eventually develop breast cancer ...

Research could lead to new ways to ID women who have higher risk of breast cancer from low-dose radiation

October 16, 2012
(Medical Xpress)—Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) have identified tissue mechanisms that may influence a woman's susceptibility or resistance to breast ...

Cancer hijack

July 19, 2013
Genetically unstable breast cancer cells appear to hijack a mechanism used by healthy stem cells to determine how they should develop into different tissues, according to new research.

A novel surface marker helps scientists 'fish out' mammary gland stem cells

April 11, 2013
Stem cells are different from all other cells in our body because they retain the remarkable genetic plasticity to self-renew indefinitely as well as develop into cell types with more specialized functions. However, this ...

Exploring the relation between stem cells and tumor growth

July 16, 2012
An EU research project has shed light on the tumor-growth role of a key-signalling pathway in mammary gland stem cells.

Changes in progenitor cell population in breast may be overlooked factor in breast cancer

December 17, 2012
The DNA mutations that accumulate over time as women age are not the sole contributor to the higher frequency of breast cancer in women over 50, Mark LaBarge, PhD, a researcher at Lawrence Berkeley National Laboratory (LBNL) ...

Recommended for you

Study prompts new ideas on cancers' origins

December 16, 2017
Rapidly dividing, yet aberrant stem cells are a major source of cancer. But a new study suggests that mature cells also play a key role in initiating cancer—a finding that could upend the way scientists think about the ...

What does hair loss have to teach us about cancer metastasis?

December 15, 2017
Understanding how cancer cells are able to metastasize—migrate from the primary tumor to distant sites in the body—and developing therapies to inhibit this process are the focus of many laboratories around the country. ...

Cancer immunotherapy may work better in patients with specific genes

December 15, 2017
Cancer cells arise when DNA is mutated, and these cells should be recognized as "foreign" by the immune system. However, cancer cells have found ways to evade detection by the immune system.

Scientists pinpoint gene to blame for poorer survival rate in early-onset breast cancer patients

December 15, 2017
A new study led by scientists at the University of Southampton has found that inherited variation in a particular gene may be to blame for the lower survival rate of patients diagnosed with early-onset breast cancer.

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.