A form of fast-spreading breast cancer has remained hard to treat despite overall advances in the field. Now a new study reveals some of the underpinnings of this disease, called basal subtype breast cancer, and may point the way to future avenues of treatments.
Women with mutations in their BRCA1 genes are more likely than others to develop basal subtype breast cancer, and the study showed that even non-cancerous cells with these mutations express, or turn on, different genes, look different under a microscope and behave differently when they divide than cells without these mutations.
That means women with BRCA1 mutations have "a reservoir of cells primed to form cancer, if the right combination of other signals comes along," said study researcher Charlotte Kuperwasser, an associate professor of Cell, Molecular & Developmental Biology at Tufts University in Boston.Normally, the BRCA1 gene suppresses tumor growth; women with mutations in this gene, however, have a much higher risk of developing breast cancer. Until now, scientists have not fully understood why.
In normal breast tissue, some cells are "milk makers" and others are "milk squeezers," and these types are easily distinguished from each other, Kuperwasser said.
But in their study, the team found that for women with BRCA1 mutations these breast cells develop abnormally, even when there are no signs of cancer. More specifically, these cell types get stuck in an immature state, Kuperwasser said.
"If you look at breast tissues under a microscope — in every way that we can do that — you cannot tell the difference between these cells," as you can in cells without the mutation, she said. And certain proteins that normally show up on the surfaces of cells of each type don't appear as they should.
In other ways, the tissue functions normally. These women have normal breast biology and normal lactation — somehow life has otherwise overcome the effects of the mutation, she said.This lack of normal maturation represents a new way of understanding the role of the BRCA1 gene, she said.
"Our understanding of tumor suppressor genes has been that they put the brakes on cell growth," Kuperwasser said. "This shows they also play an important role in normal maturation and differentiation of cells." (Differentiation is a process by which cells mature.)
"Now we can think of cancers as two different puzzles — there's the DNA damage that we know can cause cancer, but there's also the normal process of differentiation, and the regulation of that differentiation process," she said.
Future treatments
Women with BRCA1 mutations face an 80-percent chance of developing breast cancer in their lives, and many of them develop the basal subtype. Often, basal subtype cancers are particularly devastating, because they are impervious to treatments with hormone therapies.
"There's a very limited arsenal for treating basal subtype cancers," Kuperwasser said. The finding suggests scientists may want to consider therapies for basal breast cancer that target the genes involved in the differentiation of these cells.
"Even if we could convert basal cancers to luminal, hormone-responsive breast cancer, we could treat it," she said.
Further, the study shows that researchers should consider treating women with BRCA1 mutations before they develop breast cancer, she said. Therapies could be designed to coax their cells to differentiate — to get them out of their immature state — before cancer arises, she said.
"If we could normalize their breast tissue, could we lower their incidence [of breast cancer]?" she said.
Researchers may also want to study the 20 percent of women with BRCA1 mutations who don't develop breast cancer.
"What's going on in those cases, what specific mutations might be different and other factors that are involved, we don't really know,"
