Recently, in a research report published in the international journal Nature Genetics, scientists from Cambridge University and other institutions discovered for the first time that a four-stranded DNA structure (G-quadruplexes, G-quadruplexes) may play a key role in the occurrence of specific types of breast cancer. The results of related studies may provide potential new targets for the development of personalized breast cancer therapies.
In 1953, scientists Francis Crick and James Watson of the University of Cambridge published an article in the journal of Nature and proposed that the DNA in cells is a twisted double helix structure. Sixty years later, researchers Shankar Balasubramanian and Steve Jackson discovered through research that in living cells, an unusual four-stranded DNA structure may exist in the entire human genome. These structures are formed in the DNA region rich in guanine (G). When one strand of the double-stranded DNA loops outward, it will double itself and form a four-stranded "handle" in the genome, and the resulting structure is called the G-quadruplex.
Previously, researchers have developed sequencing technologies and methods to detect G-quadruplexes in DNA and chromatin, and found that G-quadruplexes play a key role in the process of DNA transcription, and at the same time it is more likely to appear in the genes of rapidly dividing cells, such as cancer cells. In this study, the researchers revealed for the first time the specific location where G-quadruplex formed in preserved breast cancer tumor tissue and breast cancer biopsy tissue. The researchers used quantitative sequencing technology to study the DNA structure of the G-quadruplex in 22 tumor models. In the process of DNA replication and cell division in cancer cells, most regions of the genome will be copied by mistake multiple times and induce copy number aberrations (CNAs).
Researchers found that the G-quadruplex structure is more common in these CNAs, especially special genes and genetic regions that play an important role in the transcription process, so it can drive tumor growth. Researcher Balasubramanian said that we are very familiar with the double helix structure of DNA, but in the past 10 years, scientists have become increasingly aware that DNA can also exist as a four-stranded structure, and it plays an important role in human biology. These four-stranded structures are especially high in rapidly sorted cells, such as cancer cells.
The abundance and location of G-quadruplexes in these biopsies can provide some clues for the study of cancer biology and the heterogeneity of breast cancer. More importantly, it also provides another potential weakness that researchers may be able to use to develop new therapies for breast cancer patients. Researchers have found that each has a different G-quadruplex pattern, and it also has a certain degree of specificity for the transcription program that drives specific breast cancer subtypes. There are 11 subtypes of breast cancer, each of which responds to different drugs in different ways.
Recognizing the special G-quadruplex pattern of tumors may help researchers identify the subtypes of breast cancer in women, thereby helping to formulate individualized targeted breast cancer therapies. Finally, the researchers said that the use of synthetic molecules to target the G-quadruplex may be able to inhibit cells from copying their DNA and block cell classification, thereby slowing uncontrolled cell proliferation at the root of cancer. In the article, the researchers also identified two molecules named pyridostatin and CX-5461, which were previously tested in a phase 1 clinical trial of BRCA2-deficient breast cancer patients.
Reference
Hänsel-Hertsch, R., Simeone, A., Shea, A. et al. Landscape of G-quadruplex DNA structural regions in breast cancer. Nat Genet (2020). doi：10.1038/s41588-020-0672-8