HER2 Overexpression Triggers an IL1α Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance

Abstract

Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers. IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. .

Synergistic interplay between PHF8 and HER2 signaling contributes to breast cancer development and drug resistance

“…838 upregulated and 536 downregulated genes by HER2 overexpression were obtained using cutoff of actual fold change of 1.5 (FC >=1.5 or <=-1.5) and adjusted p value of less than 0.05 (Supplemental Table 2). Gene Set Enrichment Analysis (GSEA) (Subramanian et al, 2005) analysis with Hallmark pathways revealed that HER2-regulated genes are significantly enriched in 18 pathways such as TNFα signaling, EMT transition, inflammatory response and mTOR ( Figure 3C and Supplemental Table 5), consistent with previous reports with similar set up (Dong et al, 2017;Liu et al, 2018b;Pradeep et al, 2012). PHF8 knockdown attenuated most of the pathways induced by HER2 overexpression ( Figure 3C and Supplemental Table 6).…”

Long noncoding RNA BHLHE40‐AS1 promotes early breast cancer progression through modulating IL‐6/STAT3 signaling

“…This analysis, rank‐ordered by P value, identifies a strong proinflammatory cytokine signature (Figure B). Two IL‐1 family members (IL‐1α and IL‐1β), IL‐6, as well as STAT3, a transcription factor downstream of all three cytokines, are found in the top seven predicted upstream regulators with activation Z ‐scores of 4.286, 3.881, 3.667, and 2.367, respectively (Figure B). These data strongly suggest that BHLHE40‐AS1 plays an important role in inflammation.…”

“…Further, while less studied in cancer than IL‐1β, IL‐1α has been found to support inflammation and cancer stem cell expansion downstream of HER2 expression. IL‐1α induces IL‐6 and STAT3 signaling creating a feed‐forward proinflammation signaling loop supporting tumor progression …”

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

“… 116 The precancerous effect of HER2 was also found to be linked to inflammation and the expansion of cancer stem-like cells (CSCs) in breast cancer. 117 A newly identified enhancer located at the 3′ gene body of HER2 was reported to be the target locus of known HER2 regulator, TFAP2C. 118 Other epigenetic mechanisms, such as DNA methylation and histone modifications, also affect this process.…”