Molecular subtype is determinant on inflammatory status and immunological profile from invasive breast cancer patients

Abstract

Breast cancer consists in a chronic inflammatory disease with multiple biological and clinical behaviors. Based on high throughput technologies data, this disease is currently classified according to the molecular expression of estrogen (ER), progesterone (PR) and human epidermal growth factor (HER-2) receptors. In this study, we defined the inflammatory profile of the main molecular subtypes of breast cancer patients: luminal (ER and PR positive, HER-2 negative), HER-2 enriched (HER-2 positive) and triple negative (ER, PR and HER-2 negative). Cytokines panel was assessed by measurement of TNF-α, TGF-β, IL-1, IL-10 and IL-12 plasmatic levels. Oxidative profile was assessed by determination of lipid peroxidation, total antioxidant capacity of plasma, malondialdehyde levels, carbonyl content and nitric oxide (NO). Clinical data were correlated with inflammatory findings. Our findings demonstrated that patients bearing the luminal subtype displayed high TNF-α, TGF-β and enhanced oxidative stress levels associated with reduced IL-12. HER-2-enriched group exhibited higher levels of TNF-α, IL-12 and TGF-β associated with enhanced oxidative stress. Triple-negative subtype exhibited the most aggressive profile of disease behavior, with reduction in both TNF-α and TGF-β, with high levels of lipid peroxidation and NO. The clinical importance of our findings lies in the fact that the inflammatory status varies in distinct ways due to molecular subtype of breast cancer, opening potential therapeutic targets to future therapies.

Fig. 1

Schematic design of the study. Luminal = ER and PR positive tumor patients, HER = ER and PR negative plus human epidermal growth factor receptor 2–enriched tumor patients, TN = triple-negative patients (estrogen, progesterone and HER-2 negative receptors)

Fig. 2

Tumor characterization. a Tumor size and b histological grade from evaluated patients. Luminal = ER and PR positive tumor patients, HER = ER and PR negative plus human epidermal growth factor receptor 2–enriched tumor patients, TN = triple-negative patients (estrogen, progesterone and HER-2 negative receptors). ^#Statistical difference between groups (p < 0.05)

Fig. 3

Cytokines status from breast cancer subtypes. a TNF-α, b IL-1β, c IL-12, d IL-10 and e TGF-β plasmatic levels. Groups were compared by Mann–Whitney’s test. Data are presented as individual distribution (gray scatters) and medians (black line). ^*Statistical difference when related to control and # when compared among subtypes (p < 0.05). CTR = Healthy controls, LUM = ER and PR positive tumor patients, HER2+ = ER and PR negative plus human epidermal growth factor receptor 2–enriched tumor patients, TN = triple-negative patients (estrogen, progesterone and HER-2 negative receptors)

Fig. 4

Oxidative stress profile. a Nitrite levels measured as estimative of NO levels, b total antioxidant capacity, c carbonyl content, d malondialdehyde levels and e lipid peroxidation of plasma from breast cancer subtypes. Data are presented as individual distribution (gray scatters) and medians (black line). Groups were compared by Mann–Whitney’s test. ^*Statistical difference when related to control and # when compared among subtypes (p < 0.05). Control = Healthy control, Luminal = ER and PR positive tumor patients, HER = ER and PR negative plus human epidermal growth factor receptor 2–enriched tumor patients, TN = triple-negative patients (estrogen, progesterone and HER-2 negative receptors)

Fig. 5

Spearman’s correlation. Only significant correlations are presented (p < 0.05). a Luminal group correlation between antioxidant capacity and age at diagnosis. b and c HER2-enriched group correlations between nitric oxide and tumor size (b) and age at diagnosis and lipid peroxidation levels (c). d Triple-negative group correlation between histological grade and TGF-beta levels. Groups were compared by Mann–Whitney’s test. HER = epidermal growth factor receptor 2–enriched tumor patients