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(-)) 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(-) 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(-) breast cancers, 
including the triple-negative phenotype.