Tamoxifen-resistant ERα positive (ERα+) breast cancers and triple-negative breast cancers represent two aggressive subgroups of mammary tumors with limited treatment options and a poor prognosis. Thus, there is still an urgent need to develop and improve targeted pharmacological treatments against these estrogen-independent cancers.

Recent data from our group suggest that the protein kinase D1 (PKD1) participates in the development and/or maintenance of the estrogen-independent phenotype in breast cancer. Indeed, up-regulating PKD1 conferred anchorage-independent growth to estrogen-dependent MCF-7 cells in the absence of β-estradiol. In addition, we found that high PKD1 mRNA levels were associated with a worse prognosis in tamoxifen-treated tumors.

PKD1 is a serine-threonine kinase encoded by the prkd1 gene and belongs to the protein kinase D (PKD) family, a novel subgroup of the calcium and calmodulin-regulated kinases (CAMK). The PKD family also includes PKD2 and PKD3 which share a high homology with PKD1.

The objective of the present study was to determine whether PKD1 could be a prognostic factor and/or a pharmacological target for the treatment of breast cancer. Expression of prkd1, prkd2 and prkd3 was analyzed by RT-qPCR in 527 breast cancer specimens (181 ERα- tumors including 102 triple negative tumors and 346 ERα+ tumors). We showed that higher prkd1 mRNA levels were associated with a lower metastasis-free survival in the overall breast cancer population (p=0.015). prkd1 prognostic value was even stronger in ERα- tumors (p=0.00042) and in triple negative tumors (p=0.0043). Conversely, prkd1 expression was not associated with prognosis in ERα+ tumors. Interestingly, high prkd2 and prkd3 mRNA levels were associated with a better prognosis in the entire cohort (p=0.0074 and p=0.028 respectively).

We have developed PKD1 inhibitors in collaboration with the AB Science pharmaceutical company and screened the ability of thirty-five compounds to inhibit anchorage-independent growth of MCF-7 cells in the absence of estrogens. The antitumor activity of two PKD1 inhibitors is currently being evaluated in vivo against patient-derived breast cancer xenografts.

In conclusion, our results show that high prkd1 expression is a bad-prognosis factor in breast cancer and that PKD1 could be a relevant therapeutic target for the treatment of breast cancer, in particular those harboring an estrogen-independent phenotype.

Citation Format: Caroline Spasojevic, Marie Regairaz, Sophie Vacher, Franck Assayag, Jean Marc Ricort, Elisabetta Marangoni, Ivan Bièche, Christian Auclair. Validation of protein kinase D1 as a prognostic factor and pharmacological target for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3121. doi:10.1158/1538-7445.AM2017-3121