Abstract
Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid-induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer.
Highlights
In most patients with cancer, mortality is linked to metastasis
After correcting for multiple testing, 28 genes corresponding to 54 Ensembl transcripts were found to be significantly downregulated, and only four transcripts were significantly upregulated in disseminated tumor cells (DTC)-positive breast cancer samples, indicating a prominent role for potential suppressors of early dissemination (Fig. 1 and Supplementary Table S2)
The results indicate that our DTC signature obtained from patients with luminal breast cancer defines a more aggressive dedifferentiated tumor population within the luminal group usually found among basal and HER2-positive patients
Summary
In most patients with cancer, mortality is linked to metastasis. To prevent the occurrence of metastasis, different chemotherapeutic agents with severe side effects are currently administered systemically. It has been shown that bone marrow is a common homing organ for DTCs of different origins, including breast, lung, and colon carcinomas [2,3,4]. Several studies, including a large-scale pooled analysis [5], have shown that the presence of even a single DTC in the bone marrow of patients with breast cancer is an independent prognostic factor [3, 5]. Several wide-ranging studies of expression profiling have shown positive correlation between the expression of the luminal markers ERα (ESR1), GATA binding protein 3 (GATA3), and forkhead box protein A1 (FOXA1) and well-differentiated breast tumors, and favorable clinical outcome [7, 8]
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