Effective targeting of estrogen receptor-negative breast cancers with the protein kinase D inhibitor CRT0066101

Sahra Borges, Edith A. Perez, E Aubrey Thompson, Derek C Radisky, Xochiquetzal J. Geiger, Peter Storz

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Invasive ductal carcinomas (IDC) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize, and their ability to resist to standard chemotherapy, hormone therapy, or HER2-targeted therapy. Using progression tissue microarrays, we here demonstrate that the serine/threonine kinase protein kinase D3 (PKD3) is highly upregulated in estrogen receptor (ER)-negative (ER<sup>-</sup>) tumors. We identify direct binding of the ER to the PRKD3 gene promoter as a mechanism of inhibition of PKD3 expression. Loss of ER results in upregulation of PKD3, leading to all hallmarks of aggressive IDC, including increased cell proliferation, migration, and invasion. This identifies ER<sup>-</sup> breast cancers as ideal for treatment with the PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment with this inhibitor targets all tumorigenic processes in vitro and decreases growth of primary tumors and metastasis in vivo. Our data strongly support the development of PKD inhibitors for clinical use for ER<sup>-</sup> breast cancers, including the triplenegative phenotype.

Original languageEnglish (US)
Pages (from-to)1306-1316
Number of pages11
JournalMolecular Cancer Therapeutics
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Protein Kinase Inhibitors
Estrogen Receptors
Breast Neoplasms
Ductal Carcinoma
Hormones
Carcinoma, Ductal, Breast
Phenotype
Protein-Serine-Threonine Kinases
Therapeutics
Cell Movement
protein kinase D
CRT 0066101
Neoplasms
Up-Regulation
Cell Proliferation
Neoplasm Metastasis
Drug Therapy
protein kinase C nu
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Effective targeting of estrogen receptor-negative breast cancers with the protein kinase D inhibitor CRT0066101. / Borges, Sahra; Perez, Edith A.; Thompson, E Aubrey; Radisky, Derek C; Geiger, Xochiquetzal J.; Storz, Peter.

In: Molecular Cancer Therapeutics, Vol. 14, No. 6, 01.06.2015, p. 1306-1316.

Research output: Contribution to journalArticle

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