Relationship between the Inflammatory Molecular Profile of Breast Carcinomas and Distant Metastasis Development

Abstract

Inflammatory conditions may promote tumor progression and aggressiveness. In previous reports, we found a group of breast cancer tumors characterized by metalloprotease-11 (MMP-11) expression by intratumoral mononuclear inflammatory cells (MICs), which was associated with distant metastasis development. Thus, in the present study we evaluated the relationship between MMP-11 expression by MICs, distant metastasis development, and a wide panel of inflammatory factors in breast carcinoma. In an initial approach, we analyzed 65 factors associated with tumor progression and inflammation, in a tumor population classified in good or bad prognosis, based on MMP-11 expression by intratumoral MICs. The most differentially expressed factors were then analyzed in a wider tumor population classified according to MMP-11 expression by MICs and also according to metastasis development. These analyses were carried out by Real-time PCR. The results showed that of the 65 starting factors analyzed, those related with MMP-11 expression by MICs were: IL-1, −5, −6, −8, −17, −18, MMP-1, TIMP-1, ADAM-8, −10, −15, −23, ADAMTS-1, −2, −15, Annexin A2, IFNβ, Claudin-3, CCL-3, MyD88, IRAK-4 and NFκB. Of them, factors more differentially expressed between both groups of tumors were IL-1, IL-5, IL-6, IL-17, IFNβ and NFκB. Thereafter, we confirmed in the wider tumor population, that there is a higher expression of those factors in tumors infiltrated by MMP-11 positive MICs. Altogether these results indicate that tumors developing worse prognosis and identified by MMP-11 expression by intratumoral MICs, shows an up-regulation of inflammatory-related genes.

Interleukin-5 Facilitates Lung Metastasis by Modulating the Immune Microenvironment

“…Increased expression of IL-5 in breast carcinomas has been linked to higher rates of development of distant metastasis and poor prognosis (29). Similarly, we reported that host-derived IL-5 is critical for formation of malignant pleural effusions induced by adenocarcinoma cells (10).…”

A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer

“…The finding that MICs express relatively abundant MMP-11 (stromalysin-3) is a strong indicator of metastatic rate, in accordance with our previous reports, 3 an expression previously reported to be associated with a high inflammatory molecular profile (highest intratumoral levels of IL-1, IL-5, IL-6, IL-17, IFNb and NFkB) in breast carcinomas. 42 An interesting question is how both CAFs and MICs maintain their defined functional state over a prolonged period of time. At least, 3 distinct mechanisms are possible: (i) genetic mutations, such as reported in studies describing p53 and PTEN mutations in the stromal compartment of breast cancer patients, [43][44] although other studies indicate that the stromal population is genetically stable in breast cancer 45 ; (ii) epigenetic alterations, or (iii) persistent environmental effects due to the presence of signals originating from cancer cells.…”

Leptin–cytokine crosstalk in breast cancer

“…Poor outcome in breast cancer has been associated with a tumor cytokine profile showing increased expression of IL-1, IL-5, IL-6, IL-17, IFN-β and NFκB (Eiro et al, 2012). IL-1 is consistently found in breast cancer biopsies and can be derived from adipocytes or tumor infiltrating macrophages.…”