Basal-like breast cancers, also known as triple-negative cancers, are an aggressive breast cancer subtype with poor treatment options. The cells of origin for luminal (cells that line the surface of the breast duct) and basal subtypes of breast cancer are not fully understood, but studies suggest that basal-like cancers can arise from luminal epithelial cells.
In a new study, researchers from Boston University Chobanian & Avedisian School of Medicine demonstrated that proper control of a cellular pathway known as the Hippo pathway prevents the development of triple negative breast cancer.
“We found that when this pathway is dysregulated or impaired, luminal epithelial cells in the mammary gland rapidly transition to a basal-like state and develop into triple negative carcinomas,” explained corresponding author Bob Varelas, Ph.D., associate professor of biochemistry.
In an experimental model, the researchers conditionally deleted the Lats1 and Lats2 genes, two components of the Hippo pathway, in the luminal epithelium of the mammary glands. When these genes were deleted, the models rapidly develop basal-like mammary carcinomas resembling human basal-like breast cancers. They found that the development of these carcinomas depended on the activity of the Hippo pathway effector proteins YAP and TAZ, and that deletion of these two proteins reversed carcinoma development in their model.
According to the researchers, the gene-expression signature identified from Lats1/2-deleted tumors could be used to identify aggressive features associated with triple negative breast cancers. Since basal-like breast cancers are notoriously difficult to treat, Varelas hopes these findings may be leveraged to help guide new directions for better treatment and improved patient outcomes. “A better understanding of the cellular mechanisms leading to the development of these cancers is essential to identifying new therapeutic options,” he said.
These findings appear online in the journal Nature Communications.
More information:
Joseph G. Kern et al, Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas, Nature Communications (2022). DOI: 10.1038/s41467-022-34864-8
Journal information:
Nature Communications
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