During pregnancy, the first cells that form the embryo must dull the maternal immune system to avoid being recognized as a foreign threat and be rejected. An aggressive form of breast cancer known as triple negative carcinoma uses a similar strategy, hijacking the immunosuppressive strategy of early embryo cells called trophoblasts to avoid being attacked by the immune system. In the case of pregnancy, the immune suppression is essential, but for patients with triple negative breast cancer (TNBC), they can counteract the ability of the body to fight cancer.
Jennifer K. Richer, PhD, University of Colorado Cancer Center investigator and Professor of Pathology, University of Colorado School of Medicine, has been studying immune-suppressive factors produced by TNBC. Dr. Richer became aware of the similarities between what the cancer cells and trophoblasts were making by learning about the causes of preterm birth in discussions with a colleague, Dr. Carole Mendelson, University of Texas Southwestern at The Endocrine Society Meeting.
“The trophoblasts, or very early cells of the fetus, dampen the mother’s immune system so that it does not recognize the fetus as being partly foreign, and our team found that cancer cells can “hijack” that program of gene expression and use it to avoid being attacked by the immune system,” says Richer.
Epithelial cells, from which carcinomas like breast cancer arise, are normally attached to each other and surrounding structures, but aggressive cancers can thrive in what Richer calls “anchorage-independent” conditions. In these “floating around” conditions the cancer cells can travel to places they should not be (metastasize), and they can evade immune attack even if they are making abnormal or mutated proteins. “In the lab, we can stimulate anchorage-independent conditions by coating the culture dishes in a way that the cancer cells can’t attach,” says Richer. “That’s when we started seeing the carcinomas cells really ramp up production of anti-death and anti-immune signals.”
Richer says, “the reasons the TNBC can make these factors a lot better than the estrogen-receptor positive breast cancer cells is the key to the whole thing.” The “molecular mimicry” of the fetal trophoblasts had been recognized previously by other researchers in multiple types of aggressive cancers, but nobody knew the mechanism that allowed the tumor cells to switch on this embryonic program.
“What we have been studying for years is that TNBC lose a particular microRNA family that is high in normal breast epithelial cells,” says Richer. In a biological system, microRNAs often sit at the ends of genes, acting as brakes that keep off the manufacture of proteins that should not be on in that particular cell type or at that point in development. In TNBC, the loss of a particular microRNA by little deletions or silencing removes the breaks to allow the inappropriate production of immune-suppressive factors.
The ER positive breast cancers can become very aggressive and metastasize, but it usually takes longer to recur as metastatic disease, if at all. On the other hand, TNBC has a peak rate of metastasis or recurrence after surgery at about 3 years.
“With Drs. Virginia Borges, Traci Lyons and Jill Slansky we are investigating whether or not the immune-suppressive factors are associated with the transient increased risk for developing breast cancer observed in recently pregnant women and/or more easily turned on in pregnancy-associated breast cancer in young women, but right now it looks like this probably can occur in cancer in older women as well,” says Richer.
Currently, the team is working to find a way to shut off these immune-suppressive factors. If successful, the research would allow additional strategies to help the patient’s immune system fight tumor cells, offering new options to complement other immunotherapies for improved outcomes for breast cancer patients.