Intra-Tumour Heterogeneity in Endocrine Resistant Metastatic Breast Cancer

Endocrine therapy is the mainstay of treatment for luminal breast cancer. Despite the widespread success of this treatment approach, a large proportion of patients develop endocrine resistance and disease recurrence leading to distant metastasis. Metastasis accounts for approximately 90% of breast cancer-related deaths. Accordingly, understanding the mechanisms that drive metastatic disease progression in endocrine resistant breast cancer is of clinical relevance. In this study, the role of heterogeneous cell populations in the development of endocrine resistant metastatic breast cancer was explored.

Fluorescence activated cell sorting (FACS) and intrinsic subtype classification using the PAM50 gene signature demonstrated that multiple subtypes are present in an ex vivo LY2 xenograft-model of endocrine resistant breast cancer. Extensive functional characterization revealed differences in proliferation, cancer stem cell activity, anchorage independent growth, and cell motility between intrinsic cell populations derived from the parent tumour. A DNA barcoding system was used to label and track cells of each subtype during primary tumour formation and metastatic progression in vivo. Overall, barcoded cells of each subtype were found to contribute to the development of distant metastasis. In particular, cells of the luminal A subtype were the most abundant cell type in metastatic tumours that developed in the bone and lung. In parallel, scRNA-seq was carried out on a subset of xenograft-derived primary tumours. Ultimately, this identified more widespread intra- and inter- tumour transcriptional heterogeneity, revealing possible mechanisms of treatment resistance and metastasis at a single cell resolution, in luminal breast cancer.

In conclusion, this study summarizes intrinsic subtype and transcriptional heterogeneity that may have biological, functional and clinical relevance in advanced, endocrine resistant breast cancer.