The results of the new study, which the Medical University of South Carolina in Charleston led, now appear in the journal Nature Communications.
The findings offer strong evidence of why some women "may be predisposed to developing radiation-induced breast cancer."
The researchers found that when levels of a tumor suppressor protein called phosphatase and tensin homolog (PTEN) were low in a type of breast tissue called stroma, it increased the likelihood that exposure to radiation would trigger tumor growth.
They also found that blocking another molecule called epidermal growth factor receptor (EGFR) might be a way to reduce the risk.
The authors suggest that specialists might be able to use levels of PTEN in breast stroma as a biomarker to predict which breast cancers are most likely to respond to radiation treatment.
"This allows," explains co-senior study author Michael C. Ostrowski, a professor in the Department of Biochemistry and Molecular Biology at the Medical University of South Carolina, "for a multi-pronged attack on the tumor, by predicting who will respond the best to radiation therapy in combination with chemotherapy and other targeted treatments."
Breast cancer and stroma tissue
Cancer develops when cells grow abnormally and form a tumor. As the tumor progresses, cells can break away and set up secondary tumors in other parts of the body. The cells of the secondary tumor bear the hallmarks of the cells in the primary tumor.
Most breast cancers start in cells of the epithelium, which is a type of tissue that lines body cavities and surfaces. In the breast, for instance, it lines the glands that make milk and the ducts that carry it.
The breast also comprises another type of tissue called stroma, which plays a "connective and supportive" role. It has been shown that healthy stroma cells can be "reprogrammed" to help tumors grow and spread.
In the United States, breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer deaths in women.
In 2015, which is the most recent year for official statistics, there were 125 new cases of breast cancer and 20 deaths from the disease for every 100,000 women in the U.S.
Low PTEN raises risk
In previous work, the researchers had described how PTEN suppresses tumor development. One way that it does this is through its effect on a "cell growth promoter" called active protein kinase B (AKT). When PTEN levels are low, AKT rises. But until the new study, it was not clear how this happened.
The researchers developed a mouse model that allowed them to investigate what happens when PTEN levels are low in breast stroma tissue. They engineered the mice to lack the gene that codes for the tumor suppressor.
They found that the breast stroma of tumor-free mice made the cells of the nearby epithelium become genetically unstable when exposed to radiation. Genetic instability is a precursor to cancer.
They also found that a single dose of radiation was enough to induce a type of abnormal growth in the breast called "focal mammary lobuloalveolar hyperplasia."
Radiation is second 'hit' trigger
Further investigation revealed that the trigger for the abnormal growth was the protein EGFR, and that blocking the protein prevented the cell changes that led to the abnormal growth.
The team then analyzed samples of breast tissue taken from patients who had undergone breast reduction surgery. They found that breast cancer was more likely to return in those patients whose breast tissue had no PTEN.
The authors note that it is unlikely that loss of PTEN by itself triggers tumor formation. They suggest that it is more likely that a second "hit" — such as exposure to radiation — is the trigger for cell changes that increase the risk of cancer.
"We may have found an Achilles heel for cancer cells, because the stromal cells and PTEN pathways can be targeted."
Prof. Michael C. Ostrowski