Open AccessBiochemical pathways mediated by KLK 6 protease in breast cancer
Author(s) -
Pampalakis Georgios,
Zingkou Eleni,
Sidiropoulos Konstantinos Gus,
Diamandis Eleftherios P.,
Zoumpourlis Vassilis,
Yousef George M.,
Sotiropoulou Georgia
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12493
Subject(s) - breast cancer , cancer research , proteomics , apoptosis , cancer , downregulation and upregulation , flow cytometry , proteases , biology , microbiology and biotechnology , enzyme , biochemistry , genetics , gene
Kallikrein‐related peptidase 6 ( KLK 6) is a serine protease normally expressed in mammary tissue and aberrantly regulated in breast cancer. At physiological levels, KLK 6 functions as a suppressor of breast cancer, while its aberrant overexpression (> 50‐fold higher than normal) is characteristic of a subset of breast cancers and has been linked to accelerated growth of primary breast tumors in severe combined immunodeficiency mice (Pampalakis et al. Cancer Res 2009, 69, 3779). Here, we investigated the molecular mechanisms underlying the concentration‐dependent functions of KLK 6 by comparing MDA ‐ MB ‐231 stable transfectants expressing increasing levels of KLK 6 in in vitro and in vivo tumorigenicity assays (soft agar, xenograft growth, tail vein metastasis). Quantitative proteomics was applied to identify proteins that are altered upon re‐expression of KLK 6 in MDA ‐ MB ‐231 at normal or constitutive levels. Overexpression of KLK 6 is associated with increased metastatic ability of breast cancer cells into lungs, increased expression of certain S100 proteins (S100A4, S100A11) and keratins (KRT), and downregulation of the apoptosis‐related proteases CASP 7 and CASP 8, and RAB s. On the other hand, KLK 6 re‐expression at physiological levels leads to inhibition of lung metastases associated with suppression of S100 proteins (S100A4, S100A10, S100A13, S100A16) and induced CASP 7 and CASP 8 expression. As this is the first report that KLK 6 expression is associated with S100 proteins, caspases, RAB s, and KRTs, we validated this finding in clinical datasets. By integrating proteomics and microarray data from breast cancer patients, we generated two composite scores, KLK 6 + S100B‐S100A7 and KLK 6 + S100B‐S100A14‐S100A16, to predict long‐term survival of breast cancer patients. We present previously unknown pathways implicating KLK 6 in breast cancer. The findings promise to aid our understanding of the functional roles of KLK 6 in breast cancer and may yield new biomarkers for the cancer types in which KLK 6 is known to be aberrantly upregulated.