Breast cancer cells dividing. Image: National Cancer Institute
Hormone receptor-positive breast cancer can spread throughout the body via the bloodstream as circulating tumor cells, or CTCs, which eventually reach remote body sites to form metastatic tumors.
The potential for these cells to form metastases rises with increased production of ribosomes, the protein-making machinery found in every living cell, according to Harvard Medical School investigators based at Massachusetts General Hospital Cancer Center.
Their work, described in a first release paper published online in Science, reveals that a subpopulation of CTCs enriched from the blood of breast cancer patients have higher levels of ribosomal proteins (RP). The presence of these proteins is associated with increased disease aggressiveness and poor clinical outcomes.
Importantly, the discovery also suggests that a combination of targeted therapies that disrupt the ribosome function and inhibit cancer cell growth slows the spread of breast cancer in a mouse model.
The study was led by Douglas Micalizzi, HMS instructor in medicine at Mass General, and co-corresponding authors Daniel Haber, the Kurt J. Isselbacher Professor of Oncology at HMS and Mass General, and Shyamala Maheswaran, HMS associate professor of surgery at Mass General.
“The Haber/Maheswaran lab has been one of the pioneers in being able to isolate, analyze and now use CTCs that are derived from patient blood samples. They offer many advantages and opportunities for understanding the metastatic pathways that are involved in advanced breast cancer,” Micalizzi said.
Aggressive subset
The team, spearheaded by first author Richard Ebright, an MD-PhD student at HMS, collected and analyzed CTCs from the blood of patients with metastatic hormone receptor-positive breast cancer and used cell lines generated from CTCs. They used CRISPR activation, a technique for studying the effect of gene activation, to screen the entire genome of the CTCs for genes that promote cancer spread.
They found that ribosomal proteins in general, and in particular one ribosomal protein, RPL15, promoted the spread of breast cancer. Patients with more aggressive breast cancer and worse survival tended to have CTCs with high levels of ribosomal proteins.
In collaboration with the lab of Shobha Vasudevan, HMS associate professor of medicine at Mass General, the team demonstrated that RPL15 alters the landscape of protein production within the CTCs.
Using a mouse model of metastatic breast cancer, the investigators tested the combination of targeted therapies consisting of an inhibitor of the ribosome and an inhibitor of cancer cell growth. They found that the combination had “dramatically increased efficacy” against RPL15 CTCs compared with other CTCs. These findings suggest that metastases might be slowed or prevented and warrants further investigation.
“These early results suggest that simultaneous therapeutic targeting of the cell translational machinery and cell proliferation pathways may merit investigation as a method to suppress an aggressive subset of CTCs that are characterized by high expression of RP genes,” the authors wrote.
The study was supported by the National Institutes of Health, Breast Cancer Research Foundation, Howard Hughes Medical Institute, National Foundation for Cancer Research, ESSCO Breast Cancer Research, National Cancer Institute, Susan G. Komen, American Cancer Society and American Society of Clinical Oncology.
Relevant disclosures can be found in the full text of the paper.
Adapted from a Mass General news release.
