DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer

Thalia Jimenez; Albert Barrios; Alexandria Tucker; Javier Collazo; Nataly Arias; Sayeda Fazel; Melanie Baker; Mariza Halim; Travis Huynh; Rajan Singh; Shehla Pervin

DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer

Am J Cancer Res. 2020 Oct 1;10(10):3487-3506. eCollection 2020.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, Charles R. Drew University of Medicine and Science 1748 118th Street, Los Angeles, CA 90059, USA.
² Department of Biology, California State University Dominguez Hills Los Angeles, CA 90747, USA.
³ Department of Obstetrics and Gynecology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA Los Angeles, CA 90095, USA.

PMID: 33163285
PMCID: PMC7642669

Abstract

Breast cancer remains a complex disease resulting in high mortality in women. A subset of cancer stem cell (CSC)-like cells expressing aldehyde dehydrogenase 1 (ALDH1) and SOX2/OCT4 are implicated in aggressive biology of specific subtypes of breast cancer. Targeting these populations in breast tumors remain challenging. We examined xenografts from three poorly studied triple negative (TN) breast cancer cells (MDA-MB-468, HCC70 and HCC1806) as well as HMLE^HRASV12 for stem cell (SC)-specific proteins, proliferation pathways and dual-specific phosphatases (DUSPs) by quantitative real-time PCR (qRT-PCR), immunoblot analysis and immunohistochemistry. We found that pERK1/2 remained suppressed in TN xenografts examined at various stages of growth, while the levels of pp38 MAPK and pAKT was upregulated. We found that DUSP was involved in the suppression of pERK1/2, which was MEK1/2 independent. Our in vitro assays, using HMLE^HRASV12 xenografts as a positive control, confirmed increased phosphatase activity that specifically influenced pERK1/2 but not pp38MAPK or pJNK levels. Family members of DUSPs examined, showed increase in DUSP9 expression in TN xenografts. Increased DUSP9 expression in xenografts was consistently associated with upregulation of SC-specific proteins, ALDH1 and SOX2/OCT4. HRAS driven HMLE^HRASV12 xenografts as well as mammospheres from TN breast cancer cells showed inverse relationship between pERK1/2 and increased expression of DUSP9 and CSC traits. In addition, treatment in vitro, with MEK1/2 inhibitor, PD 98059, reduced pERK1/2 levels and increased DUSP9 and SC-specific proteins. Depletion of subsets of SOX2/OCT4 by fluorescence-activated cell sorting (FACS), as well as pharmacological and genetic reduction of DUSP9 levels influenced ALDH1 and SOX2/OCT4 expression and reduced mammosphere growth in vitro as well as tumor growth in vivo. Collectively our data support the possibility that DUSP9 contributed to stem cell-like cells that could influence TN breast tumor growth. Conclusion: Our study shows that subsets of TN breast cancers with MEK1/2 independent reduced pERK1/2 levels will respond less to MEK1/2 inhibitors, thereby questioning their therapeutic efficacy. Our study also demonstrates context-dependent DUSP9-mediated reduced pERK1/2 levels could influence stem cell-like traits in TN breast tumors. Therefore, targeting DUSP9 could be an attractive target for improved clinical outcome in a subset of basal-like breast cancers.

Keywords: DUSP9; ERK1/2; Triple negative breast cancer; cancer stem cells.

Abstract

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