RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis

Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that is associated with significantly high mortality. In spite of advances in IBC diagnoses, the prognosis is still poor compared to non-IBC. Due to the aggressive nature of the disease, we hypothesize that elevated levels of inflammatory mediators may drive tumorigenesis and metastasis in IBC patients. Utilizing IBC cell models and patient tumor samples, we can detect elevated NF-κB activity and hyperactivation of non-canonical drivers of NF-κB (nuclear factor kappaB)-directed inflammation such as tyrosine phosphorylated receptor-interacting protein kinase 2 (pY RIPK2), when compared to non-IBC cells or patients. Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as “molecular inflammation”. Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. This would impact on the metastatic potential of IBC cells. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer.

Knockdown of RIPK2 Inhibits Proliferation and Migration, and Induces Apoptosis via the NF-κB Signaling Pathway in Gastric Cancer

“…Previous studies showed that RIPK2 plays a role in tumor progression; however, these observations were limited to carcinomas of the breast ( Zare et al, 2018 ), bladder ( Zhang and Chin, 2014 ) and colon ( Chen et al, 2020 ). To date, there is no clear evidence of the role of RIPK2 in GC.…”

“…RIPK2 is a serine/threonine/tyrosine kinase with a carboxy-terminal caspase activation and recruitment domain ( Zare et al, 2018 ), which has been identified as a oncogene participating in several process involved in the development of tumors. Although the role of RIPK2 in cancer development has been investigated, especially in colorectal cancer ( Chen et al, 2020 ), its function in GC is not yet clear.…”

“…Two important study demonstrated that Fusobacterium nucleatum , a well-recognized proinflammatory bacterium, can facilitate ulcerative colitis and promote colorectal cancer metastasis via upregulation of RIPK2 expression ( Chen et al, 2019 , 2020 ). In addition, increased RIPK2 activity contributing to inflammatory breast cancer pathogenesis and aggressiveness ( Zare et al, 2018 ). Thus, we hypothesize that RIPK2 might also serve as a biomarker for GC progression.…”

“…Our previous study demonstrated that RIPK2 was overexpressed in colorectal cancer (CRC), and, in combination with Fusobacterium nucleatum , was involved in the regulation of CRC metastases ( Chen et al, 2020 ). In addition, RIPK2 played a crucial role in the formation and progression of oral squamous cell cancer ( Wang et al, 2014 ), inflammatory breast cancer ( Zare et al, 2018 ). Nevertheless, the role of RIPK2 in GC remains unclear.…”

Erratum: Zare, A. et al. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers, 2018, 10, 184

“…The authors wish to make the following correction to their paper [ 1 ]. The name of the fourth author was misspelt.…”