How breast cancer cells enter a state of dormancy, remaining undetected for years, and why they suddenly wake up and metastasize

Good news! Perhaps, a breakthrough!

"The cells move back and forth between these stages [mesenchymal and epithelial] in a controlled and gradual process, but sometimes they go out of control, dividing rapidly and becoming malignant.

This cancer process begins when mature cells return to their earlier, developmental stage, which allows them to divide rapidly, create tumor tissue and even migrate to other tissues.

Later on, however, the cancer can benefit from exactly the opposite process: Cells that have spread throughout the body can revert to their mature state, becoming immobile and slow. Essentially, they become dormant. ...

genetically modified human breast cancer cells of the most aggressive type, called triple-negative breast cancer, to produce higher levels of OVOL proteins, which are known to be involved in the natural maturation of epithelial cells. The model showed that increasing the expression of two OVOL proteins halts the lifecycle of aggressive cancer cells and induces dormancy. In parallel, the researchers showed, in female mice implanted with human tumor tissue, that over-expression of OVOL inhibits the growth of the cancer. ...

When conditions in the body change and the level of OVOL1 drops, the cancer comes back to life and is more aggressive than ever before. ...

One key finding was that certain growth factors boost OVOL1 expression, but the steroid hormone estrogen suppresses it. The scientists went on to show that patients with low levels of estrogen receptors and high levels of OVOL1 tend to develop more aggressive cancer and have lower chances of survival. ...

One of the questions that remained unanswered was why breast cancer tends to be more aggressive when it awakens from a state of dormancy. To uncover the underlying mechanisms, the researchers traced the molecular signaling pathway through which OVOL1 induces dormancy. They discovered that this pathway triggers an accumulation of unstable molecules known as free radicals, which leads to widespread cellular damage, cell cycle arrest and dormancy. This build-up was surprising, since these molecules had not previously been linked to dormancy in cancer cells. ..."

From the editor's summary and abstract:

"Editor’s summary

Cancer can reemerge years after treatment of the primary tumor. This phenomenon is attributed to a prolonged state of cell cycle arrest called dormancy, with relapse emerging when tumor cells awaken and reenter the cell cycle. Drago-Garcia et al. identified a set of steroid- and growth factor–regulated transcription factors called OVOLs that promoted dormancy in breast cancer cells. OVOLs induced the transition of mesenchymal tumor cells to a dormant epithelial state and supported dormancy by stimulating selective autophagy but induced changes that enabled the accumulation of oxidative stress and DNA damage that can reawaken dormant cells. The findings provide insight into the factors regulating tumor dormancy and relapse. ...

fat tissue takes control of estrogen production during menopause. So, we can assume that weight gain in older women who had cancer when they were younger could increase the risk of dormant cancer resurfacing because of increased estrogen production and the associated drop in OVOL1 expression. 

Abstract

Cellular plasticity mediates tissue development as well as cancer growth and progression.

In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis.

Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology.

The expression of OVOL1 (and of OVOL2 to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, C1ORF116, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients.

We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin.

Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others).

Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence."

Wake-Up Call for Dormant Cancer - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries "...researchers reveal how breast cancer cells enter a state of dormancy, remaining undetected for years, and why they suddenly wake up and metastasize"

Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse (no public access)

Inducible re-epithelialization of cancer cells increases autophagy and DNA damage: implications for breast cancer dormancy (preprint, similar work by about the same authors, open access)

The last and the first author. (l-r) Prof. Yosef Yarden and Dr. Diana Drago-Garcia