Abstract
Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24–5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients.
Highlights
In numerous countries, breast cancer is the most common malignant neoplasm in women.Breast cancer is classified into at least six subtypes, normal-like, luminal A, luminal B, HER2-enriched, claudin-low, and basal-like, based on stringent patterns of gene expression [1,2,3].Among those, basal-like breast cancer, which exhibits stem-like properties and accounts for up to 15–20% of all breast cancers, is associated with poor outcomes [4]
We conclude that high PKCλ expression is required for ALDH1-postive cancer stem cell function and indicates a poor clinical outcome in late-stage breast cancer patients
To assess PKCλ gene alterations in breast cancer, we used two datasets: the cancer genome atlas (TCGA) dataset from oncomine, which includes data from normal tissues, and the METABRIC dataset from cBIoportal, which lacks data from normal tissues
Summary
Breast cancer is the most common malignant neoplasm in women.Breast cancer is classified into at least six subtypes, normal-like, luminal A, luminal B, HER2-enriched, claudin-low, and basal-like, based on stringent patterns of gene expression [1,2,3].Among those, basal-like breast cancer, which exhibits stem-like properties and accounts for up to 15–20% of all breast cancers, is associated with poor outcomes [4]. Breast cancer is the most common malignant neoplasm in women. Breast cancer is classified into at least six subtypes, normal-like, luminal A, luminal B, HER2-enriched, claudin-low, and basal-like, based on stringent patterns of gene expression [1,2,3]. Basal-like breast cancer, which exhibits stem-like properties and accounts for up to 15–20% of all breast cancers, is associated with poor outcomes [4]. Based on their immunohistochemically determined receptor status, breast cancers have been classified as ER and/or PgR positive type, HER2 positive type, and triple negative type (TNBC; ER and/or PgR negative, HER2 negative). About 70% of basal-like breast cancers overlap with TNBC [5,6,7,8].
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