Researchers find estrogen receptor gene fusions are a cause of breast cancer metastasis and lethal drug resistance

August 8, 2018, Baylor College of Medicine
Three-dimensional culture of human breast cancer cells, with DNA stained blue and a protein in the cell surface membrane stained green. Image created in 2014 by Tom Misteli, Ph.D., and Karen Meaburn, Ph.D. at the NIH IRP.

Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer, but resistance to therapy is common and eventual development of metastatic disease is a leading cause of death. In new research published in Cell Reports, researchers from Baylor College of Medicine and Washington University in St. Louis identify estrogen receptor alpha gene (ESR1) translocation events that drive not only therapeutic resistance, but also trigger ER+ breast cancer cells to metastasize.

"Breast is not generally thought to be a disease driven by chromosomal translocations, when two separate genes break in two and then the ends find each other to create a chimera, or fusion, protein that is encoded by the front half of one gene and the back half of another," said Jonathan Lei, graduate student in translational biology and molecular medicine at Baylor and first author on the paper. "However, we detected through RNA-sequencing the presence of ESR1 fusion transcripts in ER+ breast cancer, but we weren't sure how they contributed to disease progression."

The research team studied ESR1 fusions identified in both treatment-naive primary breast tumors, or tumors that have not yet undergone treatment, as well as in late-stage, endocrine therapy-resistant, metastatic ER+ breast cancer patients. >From the metastatic patients, the researchers found two different ESR1 fusion events that generated very active fusion proteins and went on to study their biological properties in detail.

These two hyperactive fusion proteins, part estrogen receptor and part fusion partner protein, caused profound endocrine therapy resistance because the part of the estrogen receptor that interacts with estrogen and with breast cancer drug tamoxifen was replaced with a protein fragment from the partner gene, which caused unregulated growth. More surprising was the ESR1 fusions also could promote cell motility, and cancer spread though the activation of a metastasis program called epithelial to mesenchymal transition. This potentially explains why these active ESR1 fusion genes have been found only in advanced breast cancer cases so far; they are the actual cause of metastasis.

The researchers also found a way to suppress ESR1 fusion-driven growth at primary and metastatic sites using existing FDA-approved breast cancer drugs that target CDK4/6 cell cycle proteins called palbiciclib and abemacicilib.

"These findings are important because they help explain how endocrine therapy drug resistance and metastasis are linked lethal processes. Our studies should drive more dedicated efforts to identify and characterize additional ESR1 fusions in early and late-stage ER+ breast cancer," Lei added. More ESR1 fusions are being detected in metastatic cancer, and many precision medicine programs are now including RNA-sequencing in patient care plans as sequencing technologies continue to improve and become more cost effective.

"From the clinical perspective, this study suggests that the diagnosis of an active ESR1 could guide treatment by selecting CDK4/6 inhibitor monotherapy for patients with highly endocrine therapy resistant metastatic ER positive disease where traditionally, chemotherapy has been the standard of care," said Dr. Matthew Ellis, McNair Scholar and director of the Lester and Sue Smith Breast Center, part of the NCI-designated Dan L Duncan Comprehensive Cancer Center at Baylor, and senior author on the paper.

"This research adds to the catalog of clinically actionable changes in the genome," Ellis added.

Explore further: Researchers solving treatment resistance in most common breast cancer

More information: Jonathan T. Lei et al. Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer, Cell Reports (2018). DOI: 10.1016/j.celrep.2018.07.009

Related Stories

Researchers solving treatment resistance in most common breast cancer

February 7, 2018
At Magee-Womens Research Institute (MWRI) and UPMC Hillman Cancer Center, a large team of clinical and laboratory researchers dedicated to understanding treatment resistance in the most common form of breast cancer have identified ...

PET tracer identifies estrogen receptor expression differences in breast cancer patients

August 6, 2018
In metastatic breast cancer, prognosis and treatment is largely influenced by estrogen receptor (ER) expression of the metastases. However, little is known about ER expression across metastases throughout the body and surrounding ...

Breast cancer growth signals are enhanced by a protein outside cells

July 6, 2018
New research uncovers how a sticky protein called fibronectin promotes the activity of estrogen in breast cancer cells. The study, "Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells," ...

Defects in DNA damage repair can drive treatment resistance in estrogen receptor positive breast cancers

May 28, 2018
DNA is the warehouse of genetic information in each living cell, and its integrity and stability are essential to life. This stability and integrity is maintained by DNA damage repair machinery. In a study published in Clinical ...

Study shines new light on genetic alterations of aggressive breast cancer subtype

August 7, 2014
Researchers from the Lester and Sue Smith Breast Center at Baylor College of Medicine have uncovered new information about the genetic alterations that may contribute to the development of a subtype breast cancer typically ...

Study sheds new light on mechanism of breast cancer treatment resistance

February 12, 2018
A study by researchers at Dana-Farber Cancer Institute has illuminated a specific mechanism by which estrogen receptor-positive (ER+) breast cancers can become resistant to standard therapies and metastasize.

Recommended for you

Researchers use computer model to predict prostate cancer progression

December 12, 2018
An international team of cancer researchers from Denmark and Germany have used cancer patient data to develop a computer model that can predict the progression of prostate cancer. The model is currently being implemented ...

Pushing closer to a new cancer-fighting strategy

December 11, 2018
A molecular pathway that's frequently mutated in many different forms of cancer becomes active when cells push parts of their membranes outward into bulging protrusions, Johns Hopkins researchers report in a new study. The ...

Scientists have identified and modelled a distinct biology for paediatric AML

December 11, 2018
Scientists have identified and modelled a distinct biology for paediatric acute myeloid leukaemia, one of the major causes of death in children.

HER2 mutations can cause treatment resistance in metastatic ER-positive breast cancer

December 11, 2018
Metastatic breast cancers treated with hormone therapy can become treatment-resistant when they acquire mutations in the human epidermal growth factor receptor 2 (HER2) that were not present in the original tumor, reports ...

Loss of two genes drives a deadly form of colorectal cancer, reveals a potential treatment

December 11, 2018
Colorectal cancers arise from earlier growths, called polyps, found on the inner surface of the colon. Scientists are now learning that polyps use two distinct molecular pathways as they progress to cancer, called the "conventional" ...

Successful anti-PD-1 therapy requires interaction between CD8+ T cells and dendritic cells

December 11, 2018
A team led by a Massachusetts General Hospital (MGH) investigator has found that successful cancer immunotherapy targeting the PD-1 molecule requires interaction between cytotoxic CD8+ T cells, which have been considered ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.