Precursor of breast cancer, or not?

02-05-2023

The progression of DCIS – a pre-cancerous lesion – to invasive breast cancer, which can take 10-20 years to observe in the clinic, can now be studied within one year using new mouse models.

An international team of researchers led by the Netherlands Cancer Institute developed a method to better predict the outgrowth of Ductal Carcinoma In Situ (DCIS), a possible precursor of breast cancer, into invasive breast cancer. Using mice into which cells from women with DCIS were inserted, researchers can better identify which DCIS patients are at risk for breast cancer.

The study was published in the scientific journal Cancer Cell and is part of PRECISION, a major international research project on DCIS funded by Cancer Research UK and the Dutch Cancer Society as part of Cancer Grand Challenges – a global funding initiative co-founded by Cancer Research UK and the National Cancer Institute in the US.

→ Read the publication in Cancer Cell

→ Read the interview with first author Stefan Hutten at the PRECISION website

DCIS consists of aberrant cells in the milk ducts of the breast. About 2,300 women are diagnosed with this condition a year in the Netherlands, of which approximately 80% are discovered during breast cancer screening. This is because the calcium splashes that could indicate DCIS can be seen on a breast x-ray (mammogram).

Preventing overtreatment

It still is not possible to predict which DCIS will progress to breast cancer and which will not, however, which means that virtually all women with DCIS receive preventive treatment consisting of a mastectomy or breast-conserving surgery followed by radiation and, in some countries, hormone therapy. As a result, tens of thousands of women around the world undergo intensive treatment – including the disadvantages – without any benefits. To prevent overtreatment in the future, researchers at The Netherlands Cancer Institute and the VIB-KU Leuven Center for Cancer Biology have developed a "living biobank" of DCIS cells to better understand their progression to cancer.

Following the “live” process from DCIS to breast cancer

The development from DCIS to breast cancer in humans usually takes 10 to 20 years. In the new mouse models in which human DCIS cells are inserted, this development only takes one year. It is difficult to study DCIS in patients themselves because DCIS is surgically removed fairly soon after diagnosis.

Researchers at the Netherlands Cancer Institute developed more than 100 different DCIS mouse models that allow them to accurately follow the progression from DCIS to breast cancer. DCIS cells from surgical tissue were introduced into the milk ducts of mice under anesthesia, using a very thin needle. The growth of the different DCIS cells was then tracked over a period of one year, with just under half of the mice developing invasive breast tumors. Due to the time saved, this study allowed scientists to better understand why DCIS does, or – more importantly – does not develop into breast cancer.

Research leader Jos Jonkers from the Netherlands Cancer Institute: "Thanks to our mouse models, we were able to study DCIS live for the first time. This yielded a wealth of information that allowed us to bridge a gap spanning several decades between preclinical research and the clinic."

Molecular similarities between humans and mice

While transferring tissue from women with DCIS to mice was quite an achievement in itself, the results of the study are even more interesting. Thanks to the new mouse models, researchers have gained important information about breast cancer risk factors in DCIS. For example, molecular studies showed that the presence of the HER2 protein increases the risk of breast cancer. In contrast, presence of the protein to which the hormone estrogen can bind breast cancer meant a lower risk.

3D Microscopy detects different growth patterns

After a year, half of the mouse models with DCIS were found to have developed breast cancer, while the other half did not. To study which factors had led to this distinction, the mouse models were also examined using three-dimensional microscopy by the research group of Colinda Scheele of the VIB-KU Leuven Center for Cancer Biology. By mapping the DCIS tissue cell-by-cell, the research group discovered that human DCIS cells exhibit two different three-dimensional growth patterns that can predict the risk of developing breast cancer. An example of something they discovered was that in most of the mice that did not develop breast cancer, the DCIS cells had replaced the mouse cells in the milk ducts ("replacement growth"), while when breast cancer did develop, the milk ducts had been expanded by the DCIS cells ("expansive growth").

Colinda Scheele, VIB-KU Leuven Center for Cancer Biology: “Thanks to the work of our colleagues at the Netherlands Cancer Institute, we were able to examine more than 700 samples. That we managed to distinguish which DCIS lead to breast cancer from the growth pattern is promising. If we will be able to demonstrate which DCIS cells won't develop into cancer in humans, we could potentially prevent significant physical and mental suffering.”

Images: 3D Microscopy detected different growth paths that can predict breast cancer risk. Top: expansive growth; bottom: replacement growth. DCIS cells are green; Myoepithelial cells of the milk ducts are magenta. Image by Stefan Hutten and Colinda Scheele.

Better distinguishing between harmless and high-risk DCIS

The mouse models have provided a better understanding of the biology of DCIS. This information may help to better distinguish between DCIS abnormalities that are very likely to be harmless and those DCIS abnormalities that may well grow into breast cancer in the future.

“In the first case, we could then consider not treating these women and only screening them regularly. In the second case, treatment is probably necessary to protect these women from breast cancer in time,” says Jelle Wesseling, pathologist at the Netherlands Cancer Institute and team lead for the Cancer Grand Challenges PRECISION consortium.

Unique biobank collection for science

Several mouse models are collected as a unique biobank where they can be used by scientists around the world to gather new information. The DCIS cells from these models can be frozen after outgrowth in the mouse and reintroduced into mice at a later time. Even after three generations of mice, the molecular properties of the DCIS cells appear to remain remarkably stable. PhD student Stefan Hutten, who conducted the research, said: "We now have a unique collection of nineteen distributable models representing all molecular subtypes of DCIS."

Publication: Stefan Hutten et al, 'A living biobank of patient-derived ductal carcinoma in situ Mouse-INtraDuctal xenografts identifies risk factors for invasive progression', Cancer Cell, April 27, 2023. DOI: 10.1016/j.ccell.2023.04.002

About animal research in the Netherlands Cancer Institute

Learning to understand cancer, which is an extremely complex disease involving the entire body, requires research involving living animals – which, in our institute, are rodents. We want to be open and transparent about our research involving living animals, and we conduct our research in the most responsible manner, with great care for the wellbeing of our animals. A commitment to reduce, refine and replace animal experiments, wherever possible, underpins all our work. In November 2021, the Netherlands Cancer Institute signed the nation-wide Transparency Agreement on Animal Testing. The tumor growth in this specific study involves the early stages of breast cancer, so the mice have little discomfort and no metastatic tumors yet.

About Cancer Grand Challenges

Co-founded in 2020 by two of the largest funders of cancer research in the world: Cancer Research UK and the National Cancer Institute, Cancer Grand Challenges supports a global community of diverse, world-class research teams to come together, think differently and take on some of cancer’s toughest challenges. These are the obstacles that continue to impede progress and no one scientist, institution, or country will be able to solve them alone. With awards of up to $25M, Cancer Grand Challenges teams are empowered to rise above the traditional boundaries of geography and discipline to make the progress against cancer we urgently need.

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