SIK2 restricts autophagic flux to support triple-negative breast cancer survival

Kimberly E. Maxfield, Jennifer Macion, Hariprasad Vankayalapati, Angelique W. Whitehurst

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds. This strategy returned salt inducible kinase 2 (SIK2) as essential for TNBC survival. Genetic or pharmacological inhibition of SIK2 leads to increased autophagic flux in both normal-immortalized and tumor- derived cell lines. However, this activity causes cell death selectively in breast cancer cells and is biased toward the claudinlow subtype. Depletion of ATG5, which is essential for autophagic vesicle formation, rescued the loss of viability following SIK2 inhibition. Importantly, we find that SIK2 is essential for TNBC tumor growth in vivo. Taken together, these findings indicate that claudin-low tumor cells rely on SIK2 to restrain maladaptive autophagic activation. Inhibition of SIK2 therefore presents itself as an intervention opportunity to reactivate this tumor suppressor mechanism.

Original languageEnglish (US)
Pages (from-to)3048-3057
Number of pages10
JournalMolecular and Cellular Biology
Volume36
Issue number24
DOIs
StatePublished - 2016

Fingerprint

Triple Negative Breast Neoplasms
Phosphotransferases
Salts
Survival
Breast Neoplasms
Tumor Cell Line
Cause of Death
Neoplasms
Cell Death
Pharmacology
Radiation
Drug Therapy
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

SIK2 restricts autophagic flux to support triple-negative breast cancer survival. / Maxfield, Kimberly E.; Macion, Jennifer; Vankayalapati, Hariprasad; Whitehurst, Angelique W.

In: Molecular and Cellular Biology, Vol. 36, No. 24, 2016, p. 3048-3057.

Research output: Contribution to journalArticle

Maxfield, Kimberly E. ; Macion, Jennifer ; Vankayalapati, Hariprasad ; Whitehurst, Angelique W. / SIK2 restricts autophagic flux to support triple-negative breast cancer survival. In: Molecular and Cellular Biology. 2016 ; Vol. 36, No. 24. pp. 3048-3057.
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