Abstract
Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.
Highlights
Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize
We analyzed public database (GSE5847) and found that DCN mRNA was expressed in both cancer cells and stroma, with higher expression seen in the tumor cells (Supplementary Fig. 1g). Because all of these analyses were based upon RNA expression levels, we used immunohistochemical staining to assess DCN protein expression in a tissue microarray containing 65 samples of IBC and 22 of non-IBC, locally advanced primary breast cancer (LABC)
We further showed that DCN reduces the expression of Ecadherin and EGFR, thereby inhibiting activation of EGFR
Summary
Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Several important targets and pathways have been identified, including overexpression of EGFR5, overexpression of IFITM16, RhoC7, E-cadherin[8], XIAP9, TIG1 and Axl[10], and eIFG4I11, and downregulation of TGFβ and WISP37, as well as pathways associated with enrichment of the stem cell phenotype[12,13] and angiogenesis[8] These efforts have significantly contributed to our understanding of IBC; the molecular basis for the unique and aggressive biology of IBC is still not well understood, and effective targeted therapies for this disease remain limited. In a phase II clinical trial, a humanized anti-EGFR antibody panitumumab in combination with neoadjuvant chemotherapy led to remarkably high pathological complete response rate in patients with triple-negative IBC38, indicating that
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
