Estrogen receptor positive mammary carcinoma (ER+MC) is a common type of breast cancer. It is difficult to cure as the cancer cells stop dividing but survive upon treatment leaving the cancer dormant. It then recurs years or even decades later. But scientists still don’t fully understand the molecular mechanisms underlying this process to develop new treatment for longer patient survival.

In a new paper published in Communications Medicine, novel in vivo models mimicking clinical treatment-induced ER+MC dormancy were generated by researchers at Tsinghua University.

The dormancy models display extensive dormancy features and can be used to reveal mechanisms and therapeutic targets for dormant-cell-targeted drug development. Thereafter, diverse mechanism-based treatments were determined in the generated dormancy models.

Shu Chen, the first author of the article (a PhD graduated from Tsinghua University), says the findings may be useful to abrogate dormancy responses and ameliorate clinical outcomes of ER+MC patients.

Unmet needs

Tumor dormancy is a clinical problem in treatment of ER+MC, contributing to drug resistance, metastasis, relapse, and cancer associated death. However, there are limited preclinical models for associated researches.

For instance, in vivo therapy-induced dormancy models of MC are currently limited to ER-MC and to date, no in vivo ER+MC dormancy model has been generated for therapeutic investigation, Shu says.

Tumor dormancy is highly associated with surrounding micro-environments which are not fully mimicked by in vitro generated models, and thus in vitro approaches would be expected to produce limited understanding.

“For example, in ER+MC, anti-estrogens exert multiple endocrine effects such as modulation of the IGF-1 axis, reported to promote dormant cancer cell survival” Shu explains. “Moreover, the in vivo ER models established were limited to in vivo observations and MC cells within these models were not extracted for detailed evaluation, which limited the potential applicability of such approaches in ER+MC.”

Potential approaches

To address these challenges and understand the disease progression process, Shu Chen and her colleagues mimic clinical treatment on mice to develop a new in vivo approach and generate treatment-induced dormancy ER+MC models. The dormancy associated attributes were next validated.

To maintain the dormancy attributes generated in vivo, dormancy cells were cultured in collagen-coated plates with the corresponding drug containing medium in an attempt to better replicate in vivo conditions to minimize potential loss of dormancy features.

These generated preclinical models were then used to reveal molecular basis and targets for dormant-cell-targeted therapy development.

Promising findings

It was observed that a protein, TFF3, reduced the chance of survival. This effect was proved to be associated with another protein, BCL2. Yet currently available BCL2 related drugs exhibit limited efficacy in ER+MC. Hence, TFF3 may serve as an alternate target in treatment induced dormancy to abrogate dormancy, resistance, and subsequent relapse.

A combination therapy was developed and found to be able to treat the dormant cancer. Shu uncovers the underlying synergy mechanisms that the combination treatment results in concurrent-inhibition of cell cycle progression and cell survival. The combination approach uses an experimental drug to inhibit TFF3 with clinically used drugs. These results suggest a possible treatment for people with this type of cancer.

“The in vivo approaches may be applied into extensive cancers for therapeutic target identification and drug development” Shu concludes. “The combined treatment may potentially address the clinical challenges in ER+MC dormancy and benefit patients.”