Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer

Fan Wu; Robert D McCuaig; Christopher R Sutton; Abel H Y Tan; Yoshni Jeelall; Elaine G Bean; Jin Dai; Thiru Prasanna; Jacob Batham; Laeeq Malik; Desmond Yip; Jane E Dahlstrom; Sudha Rao

doi:10.3390/ijms20123080

Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer

Int J Mol Sci. 2019 Jun 24;20(12):3080. doi: 10.3390/ijms20123080.

Authors

Fan Wu¹, Robert D McCuaig², Christopher R Sutton³, Abel H Y Tan⁴, Yoshni Jeelall⁵, Elaine G Bean⁶, Jin Dai⁷, Thiru Prasanna^{8

9}, Jacob Batham¹⁰, Laeeq Malik^{11

12}, Desmond Yip^{13

14}, Jane E Dahlstrom^{15

16}, Sudha Rao¹⁷

Affiliations

¹ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Fan.Wu@canberra.edu.au.
² Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Robert.McCuaig@canberra.edu.au.
³ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Chris.Sutton@canberra.edu.au.
⁴ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Abel.Tan@canberra.edu.au.
⁵ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Yoshni.Jeelall@canberra.edu.au.
⁶ Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra health Services, Garran ACT 2606, Australia. Elaine.Bean@act.gov.au.
⁷ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Jin.dai@canberra.edu.au.
⁸ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Thiru.Prasanna@canberra.edu.au.
⁹ Department of Medical Oncology, The Canberra Hospital, Canberra health Services, Garran ACT 2606, Australia. Thiru.Prasanna@canberra.edu.au.
¹⁰ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Jacob.batham@canberra.edu.au.
¹¹ Department of Medical Oncology, The Canberra Hospital, Canberra health Services, Garran ACT 2606, Australia. Laeeq.Malik@act.gov.au.
¹² ANU Medical School, College of Health and Medicine, The Australian National University, Canberra ACT 0200, Australia. Laeeq.Malik@act.gov.au.
¹³ Department of Medical Oncology, The Canberra Hospital, Canberra health Services, Garran ACT 2606, Australia. Desmond.Yip@anu.edu.au.
¹⁴ ANU Medical School, College of Health and Medicine, The Australian National University, Canberra ACT 0200, Australia. Desmond.Yip@anu.edu.au.
¹⁵ Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra health Services, Garran ACT 2606, Australia. Jane.Dahlstrom@act.gov.au.
¹⁶ ANU Medical School, College of Health and Medicine, The Australian National University, Canberra ACT 0200, Australia. Jane.Dahlstrom@act.gov.au.
¹⁷ Melanie Swan Memorial Translational Centre, Faculty of Sci-Tech, University of Canberra, Bruce ACT 2617, Australia. Sudha.Rao@Canberra.edu.au.

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.

Keywords: DEPArray; HER2; brain metastasis; circulating tumor cells (CTCs); dual-specificity phosphatase; single cell analysis; triple-negative breast cancer (TNBC).

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents, Immunological / pharmacology
Biomarkers, Tumor*
Brain Neoplasms / secondary*
Cell Line, Tumor
Cell Nucleus / genetics
Disease Models, Animal
Dual Specificity Phosphatase 6 / antagonists & inhibitors
Dual Specificity Phosphatase 6 / genetics*
Dual Specificity Phosphatase 6 / metabolism
Female
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic* / drug effects
Histones / metabolism
Humans
MAP Kinase Signaling System
Mice
Neoplasm Invasiveness
Neoplasm Staging
Neoplastic Cells, Circulating / metabolism
Neoplastic Cells, Circulating / pathology
Protein Binding
Protein Transport
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Single-Cell Analysis
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology*
Triple Negative Breast Neoplasms / therapy
Xenograft Model Antitumor Assays
p300-CBP Transcription Factors / metabolism

Substances

ABCB5 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
Antineoplastic Agents, Immunological
Biomarkers, Tumor
Histones
p300-CBP Transcription Factors
p300-CBP-associated factor
Receptor, ErbB-2
DUSP6 protein, human
Dual Specificity Phosphatase 6