Estrogen is directly linked to causes the copy number amplification of key cancer-causing genes in breast cancer!

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Estrogen is directly linked to causes the copy number amplification of key cancer-causing genes in breast cancer!

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Harvard scientists revealed for the first time that estrogen is directly linked to causes the copy number amplification of key cancer-causing genes in breast cancer!

Focal amplification of the copy number of key oncogenes exists in many cancers, such as MET amplification in lung cancer, HER2 amplification in breast cancer, etc., but the source of the amplification was previously unknown to the scientific community Few, let alone link copy number amplification with “external causes”.

A new study published today in “Nature” refreshes the cognition of singular cakes in this regard: The analysis of the breast cancer genome by the Harvard University research team shows that estrogen treatment can directly induce the region where the estrogen receptor is located DNA double-strand breaks, allowing cells to repair the breaks through interchromosomal rearrangement, which will become the initial event leading to local amplification of the copy number of key oncogenes such as HER2 and CCND1 [1]!

This study not only found a new mechanism for the amplification of key oncogenes, but also revealed that estrogen can directly participate in the occurrence and development of breast cancer, which refreshed the scientific community’s understanding of the carcinogenic effect of estrogen. Harvard scientists even boldly speculated, “1 One-third of breast cancers may be caused by this effect of estrogen.”

Screenshot of paper homepage

The first step of the Harvard scientists’ research was to reanalyze the genome-wide data of 780 cases of breast cancer published in the past to clarify the genes most prone to copy number amplification and the specific pattern of amplification in breast cancer, which were screened The released genes include HER2 , CCND1 and ZNF703 , ZNF217 , MYC , etc.

The mode of gene copy number amplification is dominated by local amplification (different from the duplication of the entire chromosome) , and the amplification region is also a hotspot area that is prone to interchromosomal rearrangement (called translocation/translocation in this study) , such as Among the 25 cases of breast cancer with HER2 and CCND1 amplification at the same time, translocation of chromosome 11q and 17q could be observed in 16 cases.

Major genes undergoing copy number local amplification

The researchers analyzed the amplicon (amplicon) morphology and concluded that the observed chromosomal translocations could not be explained by previously discovered mechanisms, such as break-fusion-bridge cycle (BFB) and chromosome fragmentation (chromothripsis), Rather, it is more likely to proceed in the order that translocation occurs first, followed by amplification.

For example, the HER2 gene and the CCND1 gene are located on chromosome 17q and 11q fragments respectively, and these regions happen to be high-incidence areas of chromosomal translocation, so these two genes tend to participate in translocation first and then amplify at the same time, There are many similar gene pairs.

Among the 780 cases of breast cancer included in the analysis, 244 cases (31%) had “translocation first, then amplification”, including 50% of tumors with local copy number amplification, most of which were HER2-positive and Luminal B tumors.

The researchers named this amplification mode “translocation-bridge” amplification (TB amplification) , and by reconstructing the gene variation of a specific patient, they confirmed that “translocation-bridge” amplification can simultaneously amplify key oncogene pairs. increase.

Schematic diagram of the proportion distribution of “translocation first, then amplification” and the pattern of “translocation-bridge” amplification

When further combined with the data analysis of epigenetic characteristics of breast cancer cells, the researchers were surprised to find that the hotspots of the above-mentioned gene amplification were actually related to the estrogen receptor alpha (ERα) in chromatin after cancer cells were treated with estrogen. The binding sites on are highly overlapping.

Previous studies have shown that estrogen-induced ERα binding accelerates DNA double-strand breaks at adjacent locations [2]. The researchers boldly hypothesized on this: Does estrogen directly cause chromosomal fragility (Fraglity) , and then induce the occurrence of “translocation-bridge” amplification?

With the help of CRISPR/Cas9-based high-throughput genome-wide translocation sequencing (HTGTS) technology, the researchers analyzed breast cancer cells after estrogen treatment and found that the chromosomal translocation breakpoints identified by HTGTS increased significantly, and the breakpoints Most are close to estrogen response genes.

For example, as an important target gene of estrogen, multiple DNA double-strand breaks occur near the RARA gene after estrogen treatment, and the HER2 gene happens to be in this region;

and the most commonly used method for cell repair of this double-strand break is CCND1 The chromosomal segment where the gene is located (marked as the SHANK2 gene) is translocated, which conforms to the pattern of “translocation first, then amplification”.

A brief schematic diagram of estrogen-induced translocation followed by amplification

In other words, estrogen can directly induce the amplification of the copy number of oncogenes involved in the occurrence and development of cancer.

In the past, the scientific community only knew that estrogen can promote cancer cell proliferation and prevent cell apoptosis. This is undoubtedly a discovery that refreshes cognition.

Through the analysis of pan-cancer samples (38 cancers, 2600 samples) , the researchers also pointed out that the “translocation-bridge” amplification is by no means uncommon, but the mechanism and significance in different cancers still need to be explored.

references:

[1]Lee J JK, Jung YL, Cheong TC, et al. ERα-associated translocations underlie oncogene amplifications in breast cancer[J]. Nature, 2023.

[2] Stork CT, Bocek M, Crossley MP, et al. Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage[J]. Elife, 2016, 5: e17548.

Estrogen is directly linked to causes the copy number amplification of key cancer-causing genes in breast cancer!

(source:internet, reference only)

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