Cancer biologists have identified important drivers that enable tumors to change their behavior and evade anticancer therapies.

By studying tumors in cell lines, mice and human samples, the team documented genetic signals that promote the conversion of cancer cells from one stage to another. The journal Nature Cell Biology published the research.

“Although we focused on breast cancer in this study, we believe the identified mechanism can apply to all treatment-resistant cancers,” said study senior author.

The ability of cancer cells to take different shapes, to grow faster or slower, and to vary in size is called “phenotypic plasticity.” Cancers that acquire plasticity often are more dangerous, becoming metastatic and resistant to many targeted therapies, the senior author said.

The authors show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers.

Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies.

Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. The functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes.

The team’s next step is to screen new drugs, in the form of small molecules, that disrupt the genetic signals underlying tumor plasticity. Such a drug could be administered along with current targeted therapies to eliminate the problem of resistance to those treatments, the senior author said.

“If we target the drivers of phenotypic plasticity, we may increase the effectiveness of many therapies and cure more cancers,” the author said.

https://news.uthscsa.edu/23378-2/

https://www.nature.com/articles/s41556-020-0514-z