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Major epigenetic metastasis-supressor identified for breast cancer.

The metastatic progression of breast cancer accounts for the majority of disease-related mortality. However, despite the advent of advanced technologies, the discovery of new metastasis suppressor genes that prevent the spread of breast cancer using genomic efforts has been slow due to their primary mode of regulation by epigenetic mechanisms.  Now, a study from researchers at Boston University has identified an epigenetic mechanism which plays a role in the development of breast cancer to metastatic disease.  The team state that their findings may help to predict disease progression and serve as a target for the development of future breast cancer therapies.  The opensource study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that a major rate-limiting step in metastasis is the loss of function of the metastasis suppressor genes, which block a cascade of crucial steps including the loss of adhesion of primary tumour cells and the formation of new colonies.  Despite the identification of the first metastasis suppressor gene, nonmetastatic 23 (NM23), nearly two decades ago, only a handful of new metastasis suppressors have been identified in recent years using candidate gene approaches. It is likely that the current catalog of metastasis suppressor genes remains incomplete despite the vast sequencing efforts due to the possibility that a subset of genes regulated by epigenetic mechanisms may have eluded traditional discovery procedures.  The current study reveals the importance of gene regulation by epigenetic rather than genetic mechanisms enabling the cancer cells to readily adapt to new microenvironments of the various organs of the human body at sites away from the initial sites at which the cancer cells formed.

The current study identified a gene called serum deprivation response (SDPR) and the mechanisms by which this gene is down-regulated, or silenced, in breast cancer cells promoting tumour spread. Results show, via a breast cancer progression model, that aggressively metastatic breast cancer cells had little or no genetic expression of SDPR, and that when SDPR is over-expressed, there is a significant reduction in the incidence of metastatic disease.

Data findings show that SDPR loss was not limited to breast cancer, as tumour samples from bladder, colorectal, lung, pancreatic and ovarian cancers as well as sarcomas also exhibited loss of SDPR expression based on in silico meta-analysis of publicly available data, suggesting its functional role as a metastasis suppressor is likely to impact multiple cancers.

The team surmise that their work is crucial as metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy and spreading of the cancer is the major cause of death of patients affected by breast and other cancers.  They go to add that it is of utmost importance to understand the underlying epigenetically-based molecular mechanisms that facilitate or prevent cancer metastasis.  For the future, the researchers state that while this is a significant advance in deciphering the molecular basis of the metastatic disease and may help to predict progression to metastatic cancer, its potential importance in the development of future precision cancer therapies have yet to be worked out from the identification of druggable targets regulated by SDPR.

Source: Boston University School of Medicine (BUSM)

 

Epigenetic regulation of metastatic breast cancer progression may guide prognosis and future therapy - healthinnovations

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