SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model

Abstract

Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ (DCIS) lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN are strongly associated with triple negative breast cancer. In addition, these tumor suppressors play important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory IL6/Stat3/NF-κB signaling. This resulted in generation of highly metastatic EMT-like cancer stem cells (CSCs) resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of SOCS3 resulting in low levels of this protein in basal/claudin low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors which currently lacks molecularly targeted therapies.

Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a

“…Monoclonal antibodies that blocked this receptor inhibited breast tumor proliferation and reduced circulating cancer cells, supporting the importance of this pathway in the abnormal proliferation of cells that affect the pulmonary vasculature of IPAH patients [37]. …”

Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer

“…From them, most up-regulated genes were significantly enriched for 3 pathways including focal adhesion, ECM-receptor interaction and pathway in cancer progression. These pathways in cancer progression included cytokine/NF-kB, HIF-1α, and WNT signaling, all of which are known to play a role in regulating BCSCs and have been associated with EMT [19, 33–35]. …”

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

“…22 In basal-like cancers, cytokines such as IL6 and IL8 are abundantly expressed, and promote tumor aggressiveness in both humans and mice. 4,[37][38][39] Moreover, in these tumors, NF-κB and inflammatory cytokines can enhance tumor growth by eliciting stem cell-like features and increasing the fraction of tumor-initiating cells within the population. 40,41 Our observation that EZH2 mRNA increases in RNF20-silenced basal-like cells is also consistent with their enhanced proliferation, and suggests that their differentiation state may be partly altered.…”