# The C2 Domain of PKC‑δ as a Dominant-Negative Modulator of Breast Cancer Cell Survival and Chemosensitivity

## TL;DR

The C2 domain of PKC-δ can reduce breast cancer cell survival and increase sensitivity to treatment, suggesting a new therapeutic approach.

## Contribution

The study reveals the isolated C2 domain of PKC-δ acts as a pro-apoptotic agent in breast cancer cells.

## Key findings

- Expression of the PKC-δ C2 domain reduced cell viability and increased apoptosis in both MCF-7 and MDA-MB-468 cells.
- MCF-7 cells showed G2/M arrest and increased cell size, but MDA-MB-468 cells did not.
- The C2 domain sensitized MCF-7 cells to stress consistently, while MDA-MB-468 cells required higher stress or dasatinib pretreatment.

## Abstract

Mounting evidence
implicates Protein Kinase C-δ (PKC-δ)
in breast cancer progression and therapy resistance. PKC-δ is
activated by the second messenger diacylglycerol or by proteolytic
cleavage, both of which expose the kinase’s catalytic site
and allow substrate phosphorylation. Furthermore, the C2 domain of
PKC-δ regulates the kinase by mediating intra and intermolecular
protein–protein interactions. Here, we investigated the autonomous
effects of the PKC-δ C2 domain in two breast cancer cell lines,
representing hormone-dependent and triple-negative breast cancer.
A myc-tagged PKC-δ C2 domain (myc-δC2) was stably overexpressed
in MCF-7 and MDA-MB-468 cells, and its effects on cell viability,
apoptosis, and proliferation were assessed. myc-δC2 expression
reduced cell viability and increased apoptosis in both cell lines.
In MCF-7 cells, but not in MDA-MB-468 cells, G2/M arrest and increased
cell size were observed upon myc-δC2 expression. Under oxidative
(H2O2) and genotoxic (etoposide) stress, myc-δC2
expression sensitized cells differently in the two cell lines: MCF-7
cells showed consistent sensitization, whereas in MDA-MB-468 cells,
sensitization was observed only at higher stress levels or after dasatinib
pretreatment. These results indicate a cell line-dependent pro-death
role for the isolated PKC-δ C2 domain, highlighting that modulation
of this domain, or its use as an autonomous pro-apoptotic agent, may
offer new therapeutic avenues in breast cancer.