Estrogen receptor-positive (ER+) breast cancers may respond to hormone therapy by pushing some cancer cells into a long-term dormancy, or “sleeper mode” that allows them to stay silent for potentially decades before reawakening to cause cancer relapse and metastasis, according to the results of studies headed by scientists at Imperial College London.

The researchers, working with colleagues in the U.K., Italy, and Korea, say the findings from studies in laboratory-grown cells could help to identify new strategies for either keeping these dormant cancer cells in perpetual sleeper mode, or potentially kicking them out of dormancy so that they can be killed using existing or new breast cancer therapies. “For a long time scientists have debated whether hormone therapies—which are a very effective treatment and save millions of lives—work by killing breast cancer cells or whether the drugs flip them into a dormant ‘sleeper state’,” commented Luca Magnani, PhD, from Imperial’s department of surgery.

“This is an important question as hormone treatments are used on the majority of breast cancers. Our findings suggest the drugs may actually kill some cells and switch others into this sleeper state. If we can unlock the secrets of these dormant cells, we may be able to find a way of preventing cancer coming back, either by holding the cells in permanent sleep mode, or be waking them up and killing them.” Magnani is lead author of the researchers’ published report in Nature Communications, which is titled, “Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy.”

Patients with ER+ breast cancer are treated using surgery to remove their tumor, and then receive targeted endocrine therapy (ET)—usually either an aromatase inhibitor or tamoxifen—to target the estrogen receptor. While this treatment approach does significantly delay the likelihood of cancer recurrence, about 3% of patients each year come back with relapse, which inevitably leads to cancer spread, or metastasis, the authors wrote. In fact, about 30% of breast cancer patients taking hormone therapies will eventually relapse—but sometimes not until 20 years after their initial treatment. The researchers say this long-term ET resistance represents “ … the most critical clinical problem for the management of these patients.”

Next generation sequencing (NGS) technology has shown that tumors are genetically heterogeneous, and for some cancers the level of heterogeneity is linked with the likelihood of recurrence and drug resistance. This indicates that targeted therapy may lead to the rapid expansion of genetically defined populations of resistant cells that are already present in the tumor, and which can survive and multiply when other populations of cancer cells are killed off by treatment, the researchers noted. However, this model doesn’t fit well with ER+ breast cancer, which appears to be able to stay dormant for decades.

For their study reported in Nature Communications, the team used a combination of live cell imaging, single-cell RNA sequencing (scRNA-seq), and machine learning, to examine the genetics and plasticity of ER+ breast cancer cells. Their experiments, which included about 50,000 single human breast cancer cells, involved treating cells with existing endocrine therapy. The results highlighted a small proportion of cells that were in a dormant state. These pre-adapted (PA) cells showed a unique transcriptional signature, and while they exhibited an increased ability to survive short-term endocrine therapy, they also underwent transcriptional reprogramming and genetic changes that allowed them to acquire full resistance to treatment, and allowed them to start proliferating. Further studies found evidence for the presence of these PA cells in primary tumors from patients, and in circulating tumor cell populations.

The team says the sleeper cells may provide clues as to why some breast cancers become resistant to treatment and relapse. The research, in addition, found that cells in the dormant sleeper state were more likely to spread around the body, explained Sung Pil Hong, PhD, study co-author from Imperial: “Our experiments suggest these sleeper cells are more likely to travel around the body. They could then ‘awaken’ once in other organs of the body, and cause secondary cancers.”

The team’s previous work investigating why breast cancer cells become resistant to hormone treatment suggested that cells can make their own “fuel”, so they don’t become “starved” by cancer treatment. This new research provides another piece in the puzzle, explained study co-author Iros Barozzi, PhD, who is also from the department of surgery and cancer: “These sleeper cells seem to be an intermediate stage to the cells becoming resistant to the cancer drugs. The findings also suggest the drugs actually trigger the cancer cells to enter this sleeper state.” What isn’t known yet, is how, Hong added. “ … we still don’t know how these cells switch themselves into sleep mode—and what would cause them to wake up. These are questions that need to be addressed with further research.”

“The data presented here suggest PA cells as an obligated step towards the acquisition of resistance while still requiring substantial reprogramming to recapitulate features of fully resistant,” the authors concluded. “These results highlight the multi-faceted effects of ET at single cell level, and suggest a multi-step mechanism of drug resistance that involve both non-genetic and genetic contributions … We propose that the delayed relapse common to ET-treated patients might be mediated by similar processes, in which PA-like cells are selected for and stalled by ET for up to >10 years.” The researchers suggest that further studies might investigate when during the course of treatment or cancer development these PA cells may be vulnerable to attack.

Commenting on the research, Rachel Shaw, PhD, from Cancer Research UK, said, “Although treatments for breast cancer are usually successful, cancer returns for some women, often bringing with it a poorer prognosis. Figuring out why breast cancer sometimes comes back is essential to help us develop better treatments and prevent this from happening. This study highlights a key route researchers can now explore to tackle ‘sleeping’ cancer cells that can wake up years after treatment, which could potentially save the lives of many more women with the disease.”

 

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