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MSK1 regulates luminal cell differentiation and metastatic dormancy in breast cancer

ABSTRACT: For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed the kinase MSK1 as an important regulator of metastatic dormancy. Importantly, low MSK1 expression associates with early metastasis in ER+ BCa patients. Reduced MSK1 levels impaired cellular differentiation and increased the bone homing and growth capacity of metastatic cells. MSK1 modulates chromatin status at promoters to regulate the expression of luminal differentiation genes, including those for the GATA-3 and FOXA1 transcription factors, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation by MSK1 via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa. We propose that MSK1 could be a useful marker for stratifying BCa patients as high- or low-risk for early relapse, allowing patients to receive appropriate treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100306 | GEO | 2017/11/13

SECONDARY ACCESSION(S): PRJNA391297

REPOSITORIES: GEO

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Project description:Metastatic relapse of breast cancer and other tumor types usually occurs several years after surgical resection of the primary tumor. Early dissemination of tumor cells followed by an extended period of dormancy is thought to explain this prevalent clinical behavior. By using a gain-of-function retroviral cDNA screen in the mouse, we found that Coco, a secreted antagonist of TGF-beta ligands, induces solitary mammary carcinoma cells that have extravasated in the lung stroma to exit from dormancy. Mechanistic studies demonstrate that Coco awakens dormant metastasis-initiating cells by blocking stroma-derived Bone Morphogenetic Proteins. Inhibition of canonical BMP signaling reverses the commitment to differentiation of these cells and enhances their self-renewal and tumor-initiation capacity. Expression of Coco induces a discrete gene expression signature strongly associated with metastatic relapse to the lung but not to the bone or brain in primary patientsâ samples. Accordi ngly, silencing of Coco does not inhibit metastasis to the bone or brain in mouse models. These findings suggest that metastasis-initiating cells require the self-renewal capability typically associated with stem cells in order to exit from dormancy and identify Coco as a master regulator of this process. The Affymetrix HG-U133A and Agilent platforms, which were used to build MSK82 [GSE2603], EMC192 [GSE12276], EMC286 [GSE2034], and NKI295 [van 't Veer et al., 2002; van de Vijver et al.,2002; Fan et al., 2006] datasets, do not contain probes for Coco, preventing a direct analysis of the correlation of the expression of Coco with metastatic relapse. We therefore examined the changes in gene expression caused by silencing of Coco in MDA-MB231 cells in vitro and used the resulting signature as a proxy of Coco expression. Compare the gene expression profile between shscramble with shCoco knockingdown MDA-MB231 cells Coco shRNA #2 corresponds to TRCN0000149666 and Coco shRNA #4 corresponds to TRCN0000148148.

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MSK1 regulates luminal cell differentiation and metastatic dormancy in breast cancer

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