Scientists are pulling back the veil on breast cancer and realizing that it's a far more complicated disease than anyone ever thought.
For instance, a mother has breast cancer. Then her daughter is diagnosed. This suggests a genetic link. Yet the other daughter(s) may not develop breast cancer.
And millions of women without any family history also get the dreaded disease.
"We’ve known that genetic abnormalities can cause breast cancer as in the BRCA1 and BRCA2 genes," breast cancer specialist Cary Kaufman, MD told dailyRx. "Yet those genes only account for about 5% of all breast cancer."
What about all the other breast cancers in all the other women around the world?
The growing breast cancer gene pool
New research, published in the June 21 issue of Nature, shows that the most well-known genes associated with breast cancer - the BRCA sisters - are just two of many genes that contribute to and drive breast cancer.
The findings have been surprising for a number of reasons.
In a mammoth collaboration - one of the largest to date in breast cancer - scientists have unveiled dozens of previously unknown and unsuspected genetic alterations.
Investigators from the Broad Institute of MIT, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute worked together and discovered unexpected alterations in genes that were not previously associated with breast cancer.
The team looked at the proteins in the genetic make up of 103 breast cancer tumors and DNA from normal tissue. They also sequenced all the genes in 22 tumors.
The diversity of breast cancer
One of the study authors, Matthew Meyerson, MD, PhD, talked about "the real diversity of mutations in breast cancer"
"I think it's clear there are going to be roughly 50 or so different mutated genes in breast cancer," said Dr. Meyerson, who is senior associate member of the Broad Institute and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School.
A reshuffling of two genes that are commonly seen in blood cancers have shown up in breast tumors. The surprise find is the presence of a protein called core-binding factor subunit beta (CBFB) and the absence of its partner runt-related transcription factor 1 (RUNX1).
This genetic rearrangement occurs in leukemias, but has never before been seen in solid tumor cancers.
"That's exactly the point of doing this type of analysis." said Alfredo Hidalgo Miranda, PhD, another of the paper author.
"It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process," said Dr. Miranda, who is the head of the cancer genomics laboratory at the National Institute of Genomic Medicine.
The new clue in triple-negative breast cancer
The team also uncovered a new genetic aberration in triple-negative breast cancer that may turn out to treatable with drugs currently being studied.
Triple-negative is an aggressive breast cancer that doesn't respond to conventional therapies, because it's set up differently. It doesn't have the three receptors (estrogen, progesterone or HER2) that fuel most breast cancers.
Two genes - MAGI3 and AKT3 - apparently fuse from time to time when triple-negative breast cancer forms and grows wildly in a woman's breast, the researchers found.
The good news is that this pair is now the target of experimental drugs, which could potentially lead to new treatments for currently untreatable triple-negative breast cancer.
"Triple-negative breast cancer provides an aggressive version of cancer that is worthy of all our efforts," said Dr. Kaufman, who is a breast surgeon at the Bellingham Regional Breast Center in Washington state.
"The sooner we can single out this type of breast cancer, the sooner we will save women."
The illusiveness of breast cancer
Dr. Kaufman wrote in an email what he thinks all this means for the disease and the women who experience it.
"We’ve expected that there are other genetic abnormalities causing breast cancer, but current research hasn’t found them," Dr. Kaufman said.
"Likely, the illusive genetic abnormalities would be similar to what these researchers have found. The abnormalities are subtle connections between genes which are difficult to identify.
Additional sophisticated research is needed to learn more.
"If it were simple, after all the research of the last 30 years, we’d already know the results. But, like many things, the answer is more complex than we originally thought," Dr. Kaufman said.
The many equations of breast cancer
Here's the really hard part: not only do we now know of more genes that play a role in the breast cancer story, there's also evidence that several other transgressions could also be involved.
"It may be a combination of genetic abnormalities, not a single abnormality that accounts for many of the breast cancers that we see," Dr. Kaufman said.
"Likewise, it may be genetic abnormalities COMBINED with a specific environmental state that allows the genetic abnormality to express itself."
What this means is that a woman may inherit a defective gene, but that's no certainty she will get breast cancer.
"Thus, a genetic abnormality may not always cause breast cancer, explaining why only some people in a family may get the disease while others do not," said Dr. Kaufman.
He continued, "Without sophisticated computer models and collaboration between scientists (and countries) we would not make this type of progress.
"The therapeutic model of targeted therapies awaits the discovery of appropriate sites on cancer cells that can be targeted without damaging normal tissues."
The new breast cancer answers
Dr. Kaufman notes that the study didn't specifically address the majority of breast cancer patients.
"We have always assumed that they do not have any gene abnormality. However, some of these minor and subtle genetic abnormalities being discovered may be involved in these apparent non-genetic cancers," he suggested.
"Hopefully this type of research will begin to explain why breast cancer is the most common cancer of women in the world," Dr. Kaufman said.
So the unveiling the secrets of breast cancer will continue.