Mapping the usual breast development to recognize cancer better
Breast cancer is one of the most common cancers, and some types are among the hardest to treat. The different types and presence of many different cells makes it difficult to target these tumors. Scientists at the Salk Institute have now used state-of - the-art technology to test each cell during normal breast development to understand what happens wrongly in cancer.
The results of the group, published in the Cell Reports on 8 October 2019 and distributed in a free online resource, lay the foundations for understanding normal breast growth and can lead to new strategies for tumor control.
"In order to understand what goes wrong in breast cancer, we need to first understand how normal development works," says Geoffrey Wahl, a professor in the Gene Expression Laboratory and senior author of the paper. "This study represents a major step in that direction, as we were able to profile each cell during breast development. We expect this information to be a valuable hypothesis-generating resource for the mammary gland community."
Two major cell types that are often implicated in breast cancer are found in mature breast tissue, luminary cells and basal cells. Luminal cells line the ducts and make milk while basal cells around the ducts contract to extract milk. The scientists were interested in what drives the molecular changes that control how stem cells become specialized in these cell types during growth. In particular, they explored how DNA packaging inside the cell, known as chromatin, could make certain genes accessible or unavailable to influence gene expression and growth.
"We sought to obtain a molecular map of these developing breast cells to better understand how breast tissues are formed during development and maintained during adulthood," says Christopher Dravis, a staff scientist and co-first author of the paper.
"By examining differences in chromatin accessibility, we aimed to understand which regions of the genome affected transcription, the process that involves making RNA from DNA, and how that affected cell development," adds Zhibo Ma, a postdoctoral fellow and co-first author of the paper.
To that end, the researchers compared adult and late fetal breast tissue mouse. They employed a single-cell profiling technique to separate young cells into groups with basal and luminous characteristics, based on sensitivity to chromatin. Surprisingly, every cell was already prepared to become, right before conception, either a basal or a luminal cell. This indicates that cells should rapidly become able to convert in each cell type shortly after birth with appropriate improvements in chromatin accessibility and molecular indications. The abnormal alteration may lead to the development of the tumor later. A multitude of features in each development cell were further studied by the team of bioinformatics and advanced machine learning to show a dynamic view of breast development and maturation.
In the hope of encouraging studies on cell growth, gene regulation and other factors across multiple cell type and developmental states, the Salk scientists combined their results with a free online database, widely accessible to other researchers. The authors believe that the database, which allows comparisons between accessibility of chromatin and gene expression, among other components, during normal development, could be used to develop new theories about how breast cells go wrong and cancer.
My objective has always been to help people with cancer and, by disseminating research as widely and as quickly as possible, we hope to accelerate research advancement and therapy development," says Wahl, who holds the Daniel and Martina Lewis Chair. "This study has provided us with a concrete way of understanding the steps involved in mammary development and reveals a complexity that was not evident by most other methods. We are excited to share this with the broader research community."
In the future, the authors plan to add data from more developmental time points to further develop the database of how cancer develops to hopefully lead to more effective therapies.
Other authors included Chi-Yeh Chung, Gidsela Luna and Rajshekhar R. Giraddi of Salk along with Sebastian Preissl, Olivier Poirion, Xiaomeng Hou and Bing Ren of UC San Diego.
The work was funded by the Cancer Center Core Grant (5 P30CA014195), National Institutes of Health/National Cancer Institute (R35CA197687 and CA174430), the Susan G. Komen Foundation (SAC110036), the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), the Breast Cancer Research Foundation (BCRF), the Freeberg Foundation, the Copley Foundation, the William H. Isacoff MD Research Foundation for Gastrointestinal Cancer and the Ludwig Institute for Cancer Research.
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.