High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

Abstract

Background/Aim: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. Materials and Methods: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1 high cell viability and tumor-sphere formation. Results: c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Met high PKCλ high ALDH1A3 high have a poorer prognosis than patients with c-Met low PKCλ low ALDH1A3 low. Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1 high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. Conclusion: c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer. Breast cancer is the second most frequently diagnosed cancer worldwide, and the most commonly occurring cancer among women, with 2.09 million new cases (24.2% of all cancers in women) and 0.6 million cancer-related deaths annually (1). Breast cancers are classified based on their gene expression pattern (PAM 50) into at least six subtypes, including normallike, luminal A, luminal B, HER2-enriched, claudin-low and basal-like (2-5). Among these, basal-like breast cancers have stem-like properties and a poor prognosis (4). Nonetheless, the prognosis for breast cancer patients is good overall, though it is significantly poorer for patients with late-stage tumors (stage III or IV) (6). This is in large part because late-stage breast cancers are often resistant to standard medical treatments, such as conventional surgery, chemotherapy, and radiotherapy, which is reflected in their recurrence and metastasis (6). Consequently, the new pharmacological approach to managing late-stage breast cancers is greatly needed. Tumors are composed of populations of cancer cells and distinct cancer stem cells (CSCs), which are largely undifferentiated tumorigenic cells that exhibit such stem-like properties as self-renewal and multipotency (7, 8). Most CSCs are resistant to conventional chemo-and radiotherapies, and the development of targeted therapies against CSCs is very much needed to improve clinical outcomes. CSCs within breast tumors can be identified based on their expression of CD44, CD24 and aldehyde dehydrogenase 1 (ALDH1) (9, 10). ALDH1 is an enzyme that converts aldehydes to carboxylic acids and is abundant in normal stem/progenitor cells, and various CSCs, including those in breast cancers (9, 11). Among the ALDH1 gene family, ALDH1A1 and ALDH1A3 are known to be CSC markers in several cancers (12-17). In particular, ALDH1A3 reportedly contributes significantly to the ALDH1 activity detected in breast cancer cells, and its expression correlates significantly with cancer...

Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late‑stage breast cancer

“…Gene expression data was downloaded from cBioportal and analyzed as previously described (21,41,42,53,54). Briefly, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (55,56) was downloaded from cBioPortal (cbioportal.…”

“…MCF-10A cells were grown in mammary epithelial cell growth medium (MEGM; Lonza Group, Ltd.) according to instructions from ATCC. The cancer cell lines were cultured as previously described (21,41,42,53). Mycoplasma testing was performed on all the cell lines used.…”

“…One of the atypical protein kinase C (aPKC) isotypes, PKCλ/ι, is known to be involved in cellular responses that include determination of cell polarity, as well as cell proliferation, survival, chemotaxis and migration (24)(25)(26). PKCλ is overexpressed in several types of cancer, including breast cancer (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), and is known to be involved in cancer progression, contributing to poor clinical outcomes (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). In TNBC cells, TGFβ and IL1β induce PKCλ phosphorylation and promote PKCλ-dependent proliferation, invasiveness and metastasis by inducing NF-κB p65 nuclear translocation (30).…”

“…In TNBC cells, TGFβ and IL1β induce PKCλ phosphorylation and promote PKCλ-dependent proliferation, invasiveness and metastasis by inducing NF-κB p65 nuclear translocation (30). c-Met and PKCλ are cooperatively involved in cellular viability and tumor formation in basal-like breast cancer cells (42). PKCλ is also essential for the survival of ALDH1-positive breast cancer stem cells in a caspase-3-dependent manner (41,42).…”

“…c-Met and PKCλ are cooperatively involved in cellular viability and tumor formation in basal-like breast cancer cells (42). PKCλ is also essential for the survival of ALDH1-positive breast cancer stem cells in a caspase-3-dependent manner (41,42). EGF, platelet-derived growth factor and insulin collectively activate PKCλ via PI3-kinase (43)(44)(45), and PKCλ subsequently binds to and regulates p70 S6 kinase (46).…”