Reconstructing human breast tissues in vivo

Identifying the cellular origins of breast cancer might lead to earlier diagnosis and more efficient management of the disease. Research conducted by the Convergence lab determined that common forms of breast cancer originate from breast cells known as luminal epithelial cells while rarer forms of breast cancer, such as metaplastic carcinomas, originate from basal epithelial cell types.

Clinicians and researchers classify breast cancers into subtypes based on both clinical features and molecular features, including expression of certain genes and proteins. These classifications help determine diagnosis, treatment decisions, and patient prognosis. The most common form of breast cancer, called invasive ductal carcinoma, is classified broadly into two types based on molecular features of the tumor cells: luminal-like cancers, which are sensitive to hormones, and the more aggressive basal-like cancers, which are not sensitive to hormones and tend to have a poorer prognosis.

However, there are also rare forms of breast cancer, some of which are called metaplastic carcinomas, where the cancer cells no longer resemble cells of the breast. Scientists do not yet fully understand how and why these different types of breast cancers form but one theory is that they originate from adult breast tissue stem cells.

“For the past several decades, most research efforts have been focused on discovering cancer-causing genes in hope that this information might help us discover better treatments for breast cancer. While these efforts have led to successes in treating some common forms of breast cancer, they have not provided us with information regarding where breast cancer originates and in particular, the origins of rare forms of metaplastic breast cancers for which the best course of treatment has not yet been determined,” said Kuperwasser.

In light of this, the research team chose to study the two major types of cells in the human breast, those that line the ducts and produce milk (luminal cells) and those that surround the ductal cells and contract to move the milk from the ducts (basal/myoepithelial cells) to determine whether they might form different types of breast cancers.

“We found that when basal/myoepithelial breast cells become cancerous they no longer resemble breast tissue; instead they look more like cells of the skin and form rare metaplastic breast cancers. In contrast, when luminal breast cells become cancerous, they retain the structure and molecular features of more common types of breast cancers,” said first author Patricia Keller, PhD, former post-doctoral associate.

The researchers introduced cancer-causing genes into healthy breast cells obtained from breast reduction surgeries. Using specialized markers, they were able to isolate different types of normal breast cells and evaluate how they behaved as they became cancerous in a mouse model.

“By understanding more about the cellular beginnings of cancer, we can direct our research toward investigating preventive methods and possibly even developing new therapies,” said Kuperwasser.

This study adds to the lab’s growing body of work in breast cancer research. Earlier work identified a mechanism behind the preferential formation of aggressive breast cancers in people carrying a mutated BRCA1 gene.

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