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 The
Challenge
About 55% to 72% of women who inherit a damaged (mutated) BRCA1 gene
will develop breast cancer by age 70 or 80. That’s a much higher
risk compared to women in the general population who don’t have the
mutant gene - about 13% of them will develop the disease. Plus,
people who have inherited this damaged gene tend to develop cancer
at younger ages than people who haven’t, and they’re more likely to
develop cancer in both breasts.
These high risks have long kept scientists seeking answers about why
and how BRCA1-associated breast cancer develops. They hope that a
better understanding of this cancer’s biological causes will lead to
better prevention, detection, and treatment.
About 10% of breast cancers develop in lobules and
are called invasive lobular carcinomas. Most often, breast cancers
develop in the milk ducts and are called invasive ductal carcinomas.
The word carcinoma describes tumors that start in the epithelial
cells.
Many studies have found that when a damaged BRCA1 gene leads to
breast cancer, it starts with changes in the epithelial cells that
line the inside of the ducts, called luminal cells. The specific
cells where cancer starts are often called luminal progenitor cells.
There have been fewer studies about how other types of breast cells,
particularly stromal cells, may change and contribute to the
development of cancer, especially as it relates to hereditary
genetic mutations such as BRCA1.
The Research
American Cancer Society (ACS) research scholar, Kai Kessenbrock,
PhD, studies how cells in the breast develop early changes that lead
to breast cancer, specifically BRCA1-associated breast tumors.
He recently published a study in Nature Genetics that involved mice
with an inherited mutated BRCA1 gene. The team also analyzed
pre-cancerous tissue with and without BRCA1 mutations in a 3D
cellular model in the lab.
In the past, scientists were primarily focused on BRCA1’s effect on
epithelial cells. In our lab, we found that women with germline
BRCA1 mutations have distinct precancerous changes within various
stromal cells—those cells outside of and around the ducts,"
Kessenbrock says.
“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.
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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: BRCA1-mutated 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
BRCA1-mutated 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, anti-cancer 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.
[American Cancer Society/Cancer.org]
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