October 2022

Just as trees are essential for life, the breast canal tree branches out to provide essential nourishing milk to newborns. The breast undergoes most of its development following birth under the action of the female hormones, estrogen and progesterone.

Behind the complexity and beauty of the breast, hides a clinical problem which is breast cancer. Global statistics reveal that one in 7 women will develop breast cancer, and despite advances in cancer treatment, cases continue to rise. More than 70% of all breast cancers express hormone receptors (RH+) for estrogen and/or the progesterone receptor, and are therefore “hormone-sensitive”, or “hormone-dependent”. This means that the growth of cancer cells depends on the presence of female hormones. Patients with HR+ cancer receive hormone therapy to target the estrogen receptor or hormone production. In the remaining 30% of cases, the tumor cells lack the expression of RHs (RH-) and proliferate without the presence of female hormones. This subtype being more aggressive, it proliferates faster than the RH+ subtype.

Fluorescent image showing dormant cells (in green) in mouse lung. Most cells mark the expression of the proliferation gene (in red). Blue marks cell nuclei. © Dr. Patrick Aouad and Prof. Cathrin Brisken (EPFL)

Clinical manifestations: metastases

It is important to emphasize that breast cancer is not fatal. More than 95% of mortalities are due to widespread metastases. During cancer development, tumor cells are able to spread through blood or lymph vessels and colonize other organs in the body, such as the lungs, liver, brain and bones. Compared to HR- of breast cancer, HR+ breast cancer often manifests as a dormant disease that relapses decades following the initial diagnosis. As the name suggests, a dormant state is one during which a metastatic cell stops its proliferation/growth in the colonized organ. However, this cell is still alive but inactive. It can at a given moment, under the intermediary of different signals, wake up and resume its proliferation. The mechanisms controlling dormancy and distant recurrence of HR+ tumors remain elusive due to the lack of preclinical models.

Lack of preclinical models

Despite the fact that more than 70% of breast cancer cases are HR+, this subtype remains understudied due to a lack of suitable models. When talking regarding models, we refer to adapted (in vivo) mouse models that can recapitulate clinical manifestations in women with breast cancer. Several mouse models exist for the RH- subtype; which is not the case for the RH+ subtype. The commonly used RH+ models consist of injecting millions of human tumor cells under the skin or in the fatty matter of the mammary glands of mice. These models do not recapitulate the different clinical aspects of HR+ cancer.

Thanks to a collaboration with the medical team of the Vaud University Hospital Center (CHUV) and the Lausanne Breast Network of the ICPI (International Cancer Prevention Institute), we have succeeded in establishing a new mouse model, which is called intracanal , in the laboratory of Professor Cathrin Brisken at EPFL. RH+ cancer cells are injected into the milk ducts of mice. This model mimics different aspects of the disease, the most important of which is dormancy. During my five years of PhD in the lab, I focused on the mechanisms of dormancy and the signaling pathways that allow dormant cells to wake up in the lungs.

The awakening of dormant cells

We have observed that the tumor cells that proliferate in the mammary glands of mice are in an “epithelial” state; this means that the cells are well structured and connected to each other through epithelial junctions or proteins called E-cadherin. These are on the surface of the cells and bind them, like when we cross our hands. However, the dormant cells in the lungs are now in a “mesenchymal” state: they have lost their epithelial characteristics and are no longer attached to each other. They are more elongated, lack the expression of proliferation genes and express specific genes in the “mesenchymal” state, such as the proteins ZEB1, ZEB2 and VIM. To proliferate once more, cells need to restore expression of the protein E-cadherin and return to their original epithelial state, while suppressing the “mesenchymal” state. Several signaling pathways can induce the expression of the E-cadherin protein, such as cytokines and inflammatory signaling pathways. Indeed, proliferating metastatic cells have active inflammatory signaling pathways. This opens up therapeutic avenues to prevent dormant cells from resuming their proliferation, while promoting their dormant or “mesenchymal” state. By understanding the mechanisms of dormancy, we will be able to develop therapies that target E-cadherin and prevent recurrence following several years of diagnosis. It is in this direction that our next studies are directed.

Note: the results of the research work have been published in the scientific journal “Nature Communications”.

* Dr. Patrick Aouad holds a doctorate in cell biology from the Swiss Federal Institute of Technology in Lausanne (EPFL) where he joined the laboratory of Professor Cathrin Brisken, renowned for her work on development and breast cancer. Currently, he is continuing his research on retinoblastoma and uveal melanoma at the Jules-Gonin ophthalmic hospital in Lausanne.