Roughly 85% of triple-negative breast cancers are categorized as basal-like or claudin-low carcinoma, molecular subtypes with especially poor prognosis and limited treatment options. Triple-negative breast cancers frequently harbor mutations in DNA-surveillance pathways; consequently, their overall genomic heterogeneity has been extensively characterized. By comparison, much less work has been done on the cell biology of triple-negative breast cancer. Despite the recognized histological nonuniformity of triple-negative tumors, we have only a rudimentary inventory of the types of signaling and transcriptional regulatory states that single basal-like and claudin-low cells can adopt. The long-term goal of this work is to identify and characterize the major cell-to-cell regulatory heterogeneities in triple-negative breast cancer. The current application focuses on growth-differentiation factor 11 (GDF11), a diffusible factor that is heterogeneously regulated in 3D organotypic cultures of claudin-low breast epithelial cells. Functional GDF11 bioactivity is lost in clinical cases of advanced triple-negative breast cancer, and addition of GDF11 to invasive claudin-low and basal-like cancer lines strongly suppresses invasion into basement membrane ECM. The hypothesis is that GDF11 acts a local breast-epithelial cue for proper lobular architecture, which is suppressed nongenetically during triple-negative breast cancer progression.
The aims of this proposal are: 1) To identify the signaling and transcriptional mechanisms that mediate GDF11-induced phenotypes in triple-negative breast cancer. 2) To define the key steps of GDF11 misregulation in triple-negative neoplasms. 3) To determine the impact of GDF11 on progression and metastatic colonization of triple-negative tumors. The diversity of regulatory states enables triple-negative breast cancer cells to switch and adapt rapidly during tumor progression and the evolution of drug resistance. A complete inventory of regulatory states and their transitions could one day be harnessed by novel therapies that reset intratumor regulatory heterogeneity to delay progression or resistance.
Triple-negative breast cancer has the worst prognosis of all breast cancer types. It is difficult to treat because of the lack of targeted therapies and the high nonuniformity of the cells that make up each tumor. By examining this nonuniformity at the molecular level, we can begin to consider ways to intervene that may improve prognosis.
| Bajikar, Sameer S; Wang, Chun-Chao; Borten, Michael A et al. (2017) Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer. Dev Cell 43:418-435.e13 |
