A research group from Helmholtz Zentrum München has developed an assay whereby mini-breasts in-a-dish can be grown, with cultured human breast epithelial cells rebuilt into the three-dimensional tissue architecture of the mammary gland. For this purpose, a transparent gel is used in which cells divide and spread, similar to the developing mammary gland during puberty. Specifically, cells divide and generate hollow ducts that form a network of branches and terminate in grape-like structures. The study is published in the journal Development.
In Germany, one in eight women is going to be diagnosed with breast cancer throughout her lifetime. In the past 30 years, the rate of newly diagnosed breast cancer cases has doubled. The reasons for this increase are unclear. Despite this greatly increased rate, mortality is declining steadily due to improved early detection and therapeutic options. Nonetheless, some aggressive subtypes of breast cancer remain poorly understood and incurable.
Previous studies show that throughout the reproductive lifespan of a woman, the mammary gland is constantly remodeled and renewed in order to guarantee milk production even after multiple pregnancies. Although their exact identity remains elusive, this high cellular turnover requires the presence of cells with regenerative capacity, i.e. stem cells. Breast cancer cells are shown to adopt properties of stem cells to acquire aggressive traits. To determine how aggressive traits arise in breast cancer cells, it is therefore crucial to first elucidate the functioning of normal breast stem cells. For this purpose the group provides a new powerful experimental tool.
The team explain that the aggressive behaviour of these breast cancer cells most likely originates in how the mammary gland develops and functions. The mammary gland itself consists of a structure similar in form to a bunch of grapes, a number of branching hollow ducts terminate in tiny, milk-producing pouches on one end, and the nipple on the other. This network of ducts in embedded in fatty and connective tissue which lends the breast is overall form. The mammary gland is the name-giving characteristic of mammals and provides a massive evolutionary advantage for raising offspring.
The researchers stress that from a developmental point-of-view it is therefore essential that the highly energy-intensive process of milk production kicks in after each pregnancy. It is thought that for this purpose, the mammary gland harbours stem cells that are able to regenerate the entire mammary gland. However, how exactly such stem cells contribute to the main developmental phase of the mammary gland during puberty is not entirely clear. Without doubt, aggressive breast cancer cells activate developmental processes in an uncontrolled manner, which impacts many aspects of tumor progression. In that sense, a tumour is like an uncontrolled, regenerating organ. Importantly, elucidating how these regenerative processes are normally controlled provide the basis for the development of new targeting strategies.
Using their newly developed organoid assay, the researchers observed that the behaviour of cells with regenerative capacity is determined by the physical properties of their environment. The team were able to demonstrate that increasing rigidity of the gel led to increased spreading of the cells, or, said differently, invasive growth. Similar behaviour was already observed in breast cancer cells. The results suggest that invasive growth in response to physical rigidity represents a normal process during mammary gland development that is exploited during tumour progression. The team go on to add that with their assay they can elucidate how such processes are controlled at the molecular level, which provides the basis for developing therapeutic strategies to inhibit them in breast cancer.
The researchers state that another reason the mini-mammary glands represent a particularly valuable tool is because the cells that build these structure are directly isolated from patient tissue. In this case, healthy tissue from women undergoing aesthetic breast reduction is used. The team explain that after the operation, this tissue is normally discarded. For the medical community it is an experimental treasure chest that enables them to tease out individual difference in the behaviour of stem and other cells in the human mammary gland.
The team surmise that this break-through provides the basis for many research projects, both those aimed at ways to understand how breast cancer cells acquire aggressive traits, as well as to elucidate how adult stem cells function in normal regeneration.
Source: Helmholtz Zentrum München
