Abstract
DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.
Highlights
Breast cancer is the most common malignant disease in women worldwide
We showed for the first time that nuclear-biased DUSP6 was present in circulating tumor cells (CTCs) from triple negative breast cancer (TNBC) patients
Nuclear DUSP6 was observed in brain metastases but not lung or pleura metastases from metastatic TNBC patients, while DUSP6 was always cytoplasmic in the primary tumor tissue
Summary
While there has been significant progress in breast cancer treatment over recent decades through new chemotherapies, hormone therapies, targeted therapies, and more recently immunotherapies, 25–40% of breast cancer patients still develop primary resistance and metastasis to eventually die from their disease [1,2]. Identification of predictive resistance biomarkers has so far remained elusive, especially in triple negative breast cancer (TNBC), a breast cancer molecular subtype with currently few treatment options and an often-aggressive disease course. EMT is implicated in cancer initiation, progression, metastasis, resistance to conventional therapies, and recurrence by inducing cancer stem cells (CSCs), tumor-initiating cells (TICs), and circulating tumor cells (CTCs) [3,5,6]
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