Abstract
Brain metastasis in breast cancer is particularly deadly, but effective treatments remain out of reach due to insufficient information about the mechanisms underlying brain metastasis and the potential vulnerabilities of brain-metastatic breast cancer cells. Here, human breast cancer cells and their brain-metastatic derivatives (BrMs) were used to investigate synthetic lethal interactions in BrMs. First, it was demonstrated that c-MYC activity is increased in BrMs and is required for their brain-metastatic ability in a mouse xenograft model. Specifically, c-MYC enhanced brain metastasis by facilitating the following processes within the brain microenvironment: (i) invasive growth of BrMs, (ii) macrophage infiltration, and (iii) GAP junction formation between BrMs and astrocytes by upregulating connexin 43 (GJA1/Cx43). Furthermore, RNA-sequencing (RNA-seq) analysis uncovered a set of c-MYC-regulated genes whose expression is associated with higher risk for brain metastasis in breast cancer patients. Paradoxically, however, increased c-MYC activity in BrMs rendered them more susceptible to TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis. In summary, these data not only reveal the brain metastasis-promoting role of c-MYC and a subsequent synthetic lethality with TRAIL, but also delineate the underlying mechanism. This suggests TRAIL-based approaches as potential therapeutic options for brain-metastatic breast cancer. IMPLICATIONS: This study discovers a paradoxical role of c-MYC in promoting metastasis to the brain and in rendering brain-metastatic cells more susceptible to TRAIL, which suggests the existence of an Achilles' heel, thus providing a new therapeutic opportunity for breast cancer patients.
Highlights
To successfully form distant metastases, migrating cancer cells must adapt to new microenvironments within secondary organs
We found that c-MYC function is essential for breast cancer metastasis to the brain, but increased c-MYC activity makes brain-metastatic breast cancer cells (BrM-BCC) highly sensitive to
We demonstrate that brain-metastatic derivatives (BrMs)-BCCs exhibit increased c-MYC activity, which promotes brain metastasis, and this subsequently leads to increased susceptibility to TRAIL-induced apoptosis
Summary
To successfully form distant metastases, migrating cancer cells must adapt to new microenvironments within secondary organs. This process of adaptation typically involves changes in gene expression and in the signal transduction profiles of cancer cells that will eventually give rise to the distinct features of organ-tropic metastatic cells [1]. Several genes that contribute to organ-specific metastasis have been identified, little is known about whether these genes can cause synthetic lethality in. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). J. Cha and S.K. Kim contributed to this article
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