The Living Breast Biobank
Eye on Innovation
Mayo Clinic’s Living Breast Biobank has proved invaluable in a recent breakthrough study that demonstrates a novel mechanism through which female carriers of the BRCA1 gene may be at increased risk for breast cancer. According to the study, this is because the gene contributes to poorly organized divisions of mammary progenitor cells.
“For the first time, it was possible to recreate various pathogenic BRCA1 mutations in a cell line and track living cells during their division to understand their influence on the cell division axis,” says Nagarajan Kannan, Ph.D., director of Mayo Clinic’s Stem Cell and Cancer Biology Laboratory.
The discovery, made using cell lines, was then tested to see if the mechanism was true in patients who carried a mutant BRCA gene. That’s where the Living Breast Biobank came in.
“Using biobank specimens, we were able to validate the finding and show that, in these patients who have a pathogenic BRCA mutation, that type of cell division axis is altered fundamentally,” Dr. Kannan says. “This has major consequences because the mammary progenitor cells experience several defects, including failure to orient their cell division axis because of the pathogenic germline mutation that they carry.”
The discovery is part of a collaborative research activity to understand the role of BRCA1 in mammary progenitor cell division. The collaboration was founded more than a decade ago by Dr. Kannan; lead investigator Christopher Maxwell, Ph.D., a cancer cell biologist from the University of British Columbia, Canada; and Connie Eaves, Ph.D., a preeminent stem cell scientist at the Terry Fox Laboratory in Vancouver, British Columbia.
To understand how the Living Breast Biobank supported this study means understanding its overreaching purpose and what makes it unique.
“In 2016, with support from many clinical and research colleagues, I founded this biobank to collect tissues from women who, in particular, have a germline mutation, and who undergo breast surgery at Mayo Clinic Rochester,” Dr. Kannan says.
“The protocol was later expanded to a Mayo Clinic enterprisewide collection and has become the largest living breast bank of this nature. The bank includes any gene that is associated with increased breast cancer risk, like BRCA1, BRCA2, PALB2, CHEK2, ATM, P53 —there's a whole list of genes there.”
At Mayo Clinic in Rochester, Minnesota, samples also include breast tissue from cosmetic surgeries, including living male breast tissue. “Access to living male breast tissue to study male breast cancer origin has been a major challenge, and we have solved that,” Dr. Kannan says. “One in a hundred breast cancer cases are in men, but the male mammary gland and male breast cancer remain understudied. We want to change that using the unique resource we have developed.”
Breast samples for the biobank are collected on the day a patient has surgery. Then they are brought to a central processing unit in Dr. Kannan’s lab. “It’s very labor intensive,” he says. “Every sample is freshly collected and processed, then it takes over a day and a half to generate what we call ‘epithelial stem cell-rich tissue organoids.’ These are tissue units that still have self-renewing stem cells. They are cryopreserved and then put in the bank. It is possible to ruin samples during the processing steps due to small mistakes. So there’s a whole lot of methodology optimization that went into streamlining this process.”
Many research fellows, trainees, and technologists have collectively contributed more than 10,000 hours to procure, process, and bank these stem cell-rich samples.
The expertise in isolating growth in intact stem cells is why Dr. Kannan wanted the word “living” in the biobank’s title. Surprisingly, even tissues banked from autopsies a few days after death generate living stem cells. A patient’s death does not extinguish stem cells and progenitor cells in the breast tissue, and those cells serves as a vital resource for research.
“The progenitor cells could be struggling with lack of nutrients and oxygen after patients die, but they remarkably manage to keep their cellular identity and regenerative potential intact,” says Dr. Kannan. “This phenomenon may not be shared by other tissues.”
Although autopsy samples are cryogenically frozen, the processing team is still able to purify and isolate living stem cells using expertise unique to this lab.
“All the specimens that we bank have living stem cells in them, so we can actually isolate and recreate their development process,” Dr. Kannan says.
He continues: “The other reason I use the word ‘living’ in our biobank title is to distinguish us from all other biobanks in the world that, unlike us, basically fix or freeze breast tissue in a manner unsuitable to research cellular behaviors, as it destroys stem and progenitor activity. All you can do at that point is purify biomolecules or do a histological examination, but you cannot recreate mammary development.”
Because of its focus, the Living Breast Biobank fills a specific research gap. “We do not collect tumors. Mayo Clinic already has excellent breast tumor biorepositories,” Dr. Kannan says. “We are focused on tissue that has not become a tumor, because we want to understand cellular vulnerabilities that increase risk for breast cancer — which means we want to study normal mammary gland development and deviations experienced in these developmental processes in patients at elevated risk for cancer. Our focus is to understand the early stages of breast cancer development that is typically not presented in the clinic.”
The Living Breast Biobank is capable of supporting more traditional research as well because it also banks, for example, snap frozen or formalin-fixed mammary fat or epithelial-rich stromal tissue, which Dr. Kannan calls conventional banking. “Our biobank is not just a living breast bank,” he says. “But the real value, for our money, is to process these living tissues and bank them in a viable format, which allows us to rapidly purify stem and progenitor cells and study their normal or aberrant development. This is what we did for the BRCA1 study.”
Currently, the biobank has some 500 patient samples. Each one includes an e-survey of about 150 questions from participating patients. The survey provides information on other factors that may contribute to elevated cancer risk, such as diet, lifestyle, genetics, and family and medical history.
“The know-how to bank living breast tissue exists in very few labs around the world, and none have the scale and scope for precision cancer prevention research that we offer,” Dr. Kannan says. “We have actually done this in a biobanking mode, meaning that all our samples were processed with a lot of rigor and quality controls. With a lot of gratitude toward our patients and families who have participated in the biobank, we look forward to an exciting era of team science with both internal and outside partners to address grossly unmet needs in breast cancer prevention research.”
This unique Mayo Clinic resource offers a novel portal into the study of gene mutations before they cause breast cancer.
As Mayo Clinic’s Anatomic Pathology moves from traditional glass slides to digital images, the advance in technology is achieving clear benefits in collaboration, learning, and patient care.
In a world of ever-faster technical change, Mayo Clinic Laboratories is uniquely positioned to innovate. Collaboration with clinicians pinpoints unmet patient needs and facilitates the development of diagnostic testing that provides answers.