Page 85 2024 PAINT THE PAPER PINK Lincoln Daily News Oct/Nov 2024 “That means the epithelial cell may be the first place hereditary breast cancer starts, but something else—in the stroma, we think—is influencing those epithelial cells to mutate,” he explains. Kessenbrock and his team found that breast tissue with a mutated BRCA1 gene but without any cancer present had many more luminal progenitor cells that had changed from their normal state. The cells also had more genes prompting tumor cells to grow rapidly. The team found two striking differences between human cells in their lab that were BRCA1-mutation carriers and that were noncarriers: In BRCA1-mutated carriers, cells that help make up the connective tissue in the stroma - called fibroblasts - had a cancer-associated type (known as a CAF) before any cancer had developed. Those BRCA1-mutated fibroblasts had higher amounts of the gene that codes for the enzyme MMP3 (matrix metalloproteinase), which promotes breast cancer during aging and increases genetic instability. The researchers also revealed something that had been completely unknown: BRCA1mutated carriers had more MMP3-positive stromal cells close to epithelial structures, suggesting a direct link between MMP3 and an increased risk of developing breast cancer. Plus, the increase in MMP3 was “particularly significant” around the lobules. The study authors note that this location could indicate that tumors with a BRCA1 mutation may start “predominately in lobular rather than ductal regions.” They had similar findings in their mouse studies. Why Does It Matter? Kessenbrock’s findings about MMP3 levels in the breast stroma and its location add new evidence to other reports that point to BRCA1mutated breast cancers starting in luminal progenitor cells. More studies still need to be done, but Kessenbrock is hopeful. “Our findings that stromal cells cause hereditary breast cancer in mice may help lead to new ways of monitoring and treating people with BRCA1 mutations. What’s more, anticancer drugs that block the effects of MMP3 may one day have the potential to prevent these breast cancers in women with high-risk BRCA1 mutations,” he says. Past studies using MMP3 inhibitor drugs have not shown promising results. But the study authors note that those trials focused on people with late-stage cancers. To learn how well targeting stromal-epithelial interactions might work requires a study designed to include people with a mutated BRCA1 gene who have not developed cancer.
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