Featured Article October 01, 2020

Virtual forum: New strategies for tackling breast cancer

Understanding duplication in certain genes may be the key to creating personalized cancer care for patients with triple-negative breast cancer, scientists from The Jackson Laboratory (JAX) shared during a JAXtaposition virtual event.

“It really depends on the type of treatment, but the whole research field is trying to move away from chemotherapy and towards more specific approaches that would be much more effective specifically on cancer cells and have fewer side effects for the normal cells,” said Francesca Menghi, Ph.D.Studies critical genomic changes implicated in ovarian and breast cancers.Francesca Menghi, Ph.D., associate research scientist in the  The Liu LabResearching the fundamental genomics of breast cancer.Liu lab.

Menghi studies critical genomic changes implicated in ovarian and breast cancers, with the goal of a better understanding of the individuality of cancer genomes and the development of novel approaches toward the personalized management of cancer patients.

“Precision comes from understanding how to take a surgical strike against the signaling pathway or the growth-promoting feature of the cancer cells, specifically, without targeting everything else that's present in all the other cells in the body,” added Professor Mark Adams, Ph.D.Development and application of approaches for human and mouse microbiome analysis and genomic analysis of the evolution of Gram-negative pathogens.Mark Adams, Ph.D., deputy director of The Jackson Laboratory for Genomic Medicine, who moderated the discussion. Adams also serves as director of clinical diagnostic research at the Laboratory.

“That's really where the promise is, is understanding that basic science that leads to how is it that the cancer cell stays alive and progresses, and being able to target that correctly,” he said.

Interrogating the cancer genome

Menghi and her colleagues have been focused on studying breast and ovarian cancer genomics, using a combination of experimental research and computational work.

“We need to appreciate the complexity of cancer cells to understand what are the very first steps that lead to the transformation of a normal cell into a cancer cell, and to be able to distinguish different forms of cancer,” said Menghi. “Even though they might originate in the same organ, they can be very different, so we're trying to really distinguish different subtypes. And with that in mind, we also want to optimize treatments for patients.”

The team’s experimental research involves the use of cancer models such as cell lines that they can grow and study in the laboratory, as well as mouse models of breast cancer, and patient-derived xenografts (human tumor tissues that are engrafted in immuno-compromised mice). They then use their computational expertise to analyze the large amount of genomic data that is generated to understand the specific changes that occur within a cancer cell.

With this integration of the wet lab and the dry lab, “our ability right now to interrogate the cancer genome is incredible,” she said.

The ABCs of the human genome

Menghi uses a very simple metaphor to describe how cancer is a disease of the DNA: our genetic code can be seen as a four-letter alphabet (A, T, C, G, which represent our nucleotides) that makes up short, three-letter words (called codons), and the combination of these three-letter words turn into sentences (our genes). “These sentences can be long or short, they can be more or less complex, and it’s estimated that we have roughly 30,000 genes in our genome,” explained Menghi. Following Menghi’s metaphor, these “sentences,” or genes, are organized into chapters (chromosomes). We have 46 chromosomes in every one of our somatic cells, and the totality of all the DNA contained in these 46 chromosomes represent our genome.

When we talk about the cancer genome or cancer genomics, we actually refer to the study of the entire alphabet, that is contained in our cells, she said, these billions of letters that are organized into words, sentences, and chapters.

“A cancer cell is really just a normal cell where changes in these sentences have occurred, and so that cell starts behaving differently,” she said.

Duplications: The key to personalized cancer care? 

Menghi and her colleagues are particularly interested in studying DNA duplications, where an extra copy of a segment of DNA that can either emphasize or disrupt a certain gene’s activity, depending on its size and location. The team found that duplications are incredibly common in the cancer genome of a specific subset of breast cancer patients: those with triple-negative breast cancer (which means the tumors are negative for estrogen and progesterone receptors, and HER2 receptor). “In roughly 50% of cases, we saw hundreds of duplications that were scattered throughout the genome,” she said.

Given the lack of specific targeted therapies that are available for this cancer, “We really wanted to understand better how this triple-negative breast cancer originates: what drives its growth? What can we do to improve the clinical management of triple-negative breast cancer patients?”

The researchers found that the overall effect of those hundreds of duplications was a genome-wide imbalance that ultimately drives cell transformation into tumor cells. Menghi says that with this information, researchers can start to identify what the original genetic drivers of the duplications are, and then develop or simply optimize treatments in a more specific and personalized manner.

“Our vision, and not just our lab’s vision, but the entire research community’s vision for cancer therapy, is that cancer patients are not just treated based on the organ of origin of their cancers, but that they are really recognized for the specific DNA alterations that occur in their cancer genomes. “When we can start stratifying patients based on specific DNA changes and alterations, and then subgroup them and define what their optimal treatment is going to be, we will have a truly personalized care clinical setting,” she said.