RHAMM splice variants confer radiosensitivity in human breast cancer cell lines

Abstract

Biomarkers for prognosis in radiotherapy-treated breast cancer patients are urgently needed and important to stratify patients for adjuvant therapies. Recently, a role of the receptor of hyaluronan-mediated motility (RHAMM) has been suggested for tumor progression. Our aim was (i) to investigate the prognostic value of RHAMM in breast cancer and (ii) to unravel its potential function in the radiosusceptibility of breast cancer cells. We demonstrate that RHAMM mRNA expression in breast cancer biopsies is inversely correlated with tumor grade and overall survival. Radiosusceptibility in vitro was evaluated by sub-G1 analysis (apoptosis) and determination of the proliferation rate. The potential role of RHAMM was addressed by short interfering RNAs against RHAMM and its splice variants. High expression of RHAMMv1/v2 in p53 wild type cells (MCF-7) induced cellular apoptosis in response to ionizing radiation. In comparison, in p53 mutated cells (MDA-MB-231) RHAMMv1/v2 was expressed sparsely resulting in resistance towards irradiation induced apoptosis. Proliferation capacity was not altered by ionizing radiation in both cell lines. Importantly, pharmacological inhibition of the major ligand of RHAMM, hyaluronan, sensitized both cell lines towards radiation induced cell death. Based on the present data, we conclude that the detection of RHAMM splice variants in correlation with the p53 mutation status could help to predict the susceptibility of breast cancer cells to radiotherapy. Additionally, our studies raise the possibility that the response to radiotherapy in selected cohorts may be improved by pharmaceutical strategies against RHAMM and its ligand hyaluronan.

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

“…The second important HA receptor, RHAMM, is a coiled-coil type protein expressed both in the cytoplasm and on cell membranes, as well as in the cytoskeleton and nucleus. Like CD44, RHAMM undergoes alternative splicing as truncated isoforms were detected in tumor cells [ 83 ], and it has been reported to be highly expressed in several tumors, including breast, colon, brain, prostate, and endometrial [ 84 , 85 , 86 , 87 ]. After binding HA, RHAMM interacts with other receptors such as PDGFR, TGFβ receptor I (TGFβRI), and CD44 [ 75 ], thus inducing inflammatory pathways through ERK1/2 leading to cell migration, wound healing, tumorigenesis, and EMT.…”

The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer

“…Overexpression of RHAMM has been linked to disease progression in many solid [ 15 , 16 ] and haematological cancers [ 17 ]. We have previously described RHAMM as an independent adverse prognostic factor in mismatch repair (MMR) proficient tumors in a cohort of 1420 CRC patients [ 18 ].…”

RHAMM Is a Multifunctional Protein That Regulates Cancer Progression

“…These show that elevated RHAMM expression is characteristic of most cancers and prognostic of a poor outcome in many. For example, elevated RHAMM expression is an indicator of poor prognosis in breast cancer [ 119 , 120 , 121 ], multiple myeloma [ 122 ], oral squamous cell carcinoma [ 123 ], ovarian cancer [ 124 ], lung cancer [ 125 ], prostate cancer [ 126 ], colon cancer [ 127 ], and gastric cancer [ 128 ]. However, histology analyses of these human tumors reveal that RHAMM expression is heterogeneous, and high RHAMM expression is often limited to a small subset of cancer cells [ 119 ].…”