Cytoplasmic colocalization of RXRα and PPARγ as an independent negative prognosticator for breast cancer patients

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease

Prognostic relevance of nuclear receptors in relation to peritumoral inflammation and tumor infiltration by lymphocytes in breast cancer

The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p 15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC

Interleukin 15 and Eotaxin correlate with the outcome of breast cancer patients vice versa independent of CTC status

BACKGROUND Circulating tumor cells (CTC) in the peripheral blood in women with breast cancer has been found to be an indicator of prognosis before the start of systemic treatment. The aim of this study is the assessment of specific cytokine profiles as markers for CTC involvement that could act as independent prognostic markers in terms of survival outcome for breast cancer patients. METHODS Patients selected for this study were defined as women with breast cancer of the SUCCESS study. A total of 200 patients' sera were included in this study, 100 patients being positive for circulating tumor cells (CTC) and 100 patients being CTC negative. The matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification, and patient survival. Commercial ELISA with a multi cytokine/chemokine array was used to screen the sera for Interleukin 15 (IL-15) and eotaxin. RESULTS Statistically significant concentrations were exposed for IL-15 levels regardless of the CTC-Status, lymph node involvement, or hormone receptor status. Significantly enhanced serum IL-15 concentrations were observed in those patients with worse overall survival (OS) and disease-free survival (DFS). Elevated serum concentrations of IL-15 significantly correlate with patients diagnosed with Grade 3 tumor and worse OS. In contrast, patients with a Grade 3 tumor with a favourable OS and DFS demonstrated significantly decreased IL-15 values. The CTC negative patient subgroup with a favourable OS and DFS, showed statistically significant elevated eotaxin values. CONCLUSION These findings suggest a potential functional interaction of increased IL-15 concentrations in the peripheral blood of patients with a worse OS and DFS, regardless of prognostic factors at primary diagnosis. The increased levels of the chemokine eotaxin in CTC negative patients and a favourable OS and DFS, on the other hand, suggest that the overexpression inhibits CTCs entering the peripheral blood, thus emphasizing a significant inhibition of circulation specific metastasis. To sum up, IL-15 could be used as an independent prognostic marker in terms of survival outcome for breast cancer patients and used as an early indicator to highlight high-risk patients and consequently the adjustment of cancer therapy strategies

Regulatory T cell apoptosis during preeclampsia may be prevented by Gal-2

There are several open questions to be answered regarding the pathophysiology of the development of preeclampsia (PE). Numerous factors are involved in its genesis, such as defective placentation, vascular impairment, and an altered immune response. The activation of the adaptive and innate immune system represents an immunologic, particularity during PE. Proinflammatory cytokines are predominantly produced, whereas immune regulatory and immune suppressive factors are diminished in PE. In the present study, we focused on the recruitment of regulatory T cells (Tregs) which are key players in processes mediating immune tolerance. To identify Tregs in the decidua, an immunohistochemical staining of FoxP3 of 32 PE and 34 control placentas was performed. A clearly reduced number of FoxP3-positive cells in the decidua of preeclamptic women could be shown in our analysis (p = 0.036). Furthermore, CCL22, a well-known Treg chemoattractant, was immunohistochemically evaluated. Interestingly, CCL22 expression was increased at the maternal-fetal interface in PE-affected pregnancies (p(syncytiotrophoblas)(t) = 0.035, p(decidu)(a) = 0.004). Therefore, the hypothesis that Tregs undergo apoptosis at the materno-fetal interface during PE was generated, and verified by FoxP3/TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining. Galectin-2 (Gal-2), a member of the family of carbohydrate-binding proteins, which is known to be downregulated during PE, seems to play a pivotal role in T cell apoptosis. By performing a cell culture experiment with isolated Tregs, we could identify Gal-2 as a factor that seems to prevent the apoptosis of Tregs. Our findings point to a cascade of apoptosis of Tregs at the materno-fetal interface during PE. Gal-2 might be a potential therapeutic target in PE to regulate immune tolerance

Placental expression of inflammatory Galectin-12 is associated with gestational diabetes

Objectives Gestational diabetes mellitus (GDM) is a growing health concern. Since members of the galectin-family are identified to play a role in the pathogenesis of GDM, we determined galectin-12 as an essential protein due to its influence in lipolysis and inflammation processes. This study investigates the expression of galectin-12 in the placentas of women with GDM. Study design The study population includes 40 expectant women suffering from GDM and 40 healthy controls. The expression of galectin-12 in the syncytiotrophoblast (SCT) and the extra villous trophoblast (EVT) of the placenta was analyzed by immunohistological staining and double immunofluorescence. Immunoreactivity Score (IRS) was used for evaluation. Results The results demonstrate a significant overexpression of galectin-12 in the nucleus of the SCT and the EVT of placentas with GDM compared to the healthy control group. Additionally, double immunofluorescence visualizes corresponding results with an overexpression of galectin-12 in the extra villous trophoblast of GDM placentas representing maternal cells. Conclusion This study identifies galectin-12 to be associated with the process of gestational diabetes mellitus. These findings are in correspondence with the involvement of galectin-12 in inflammatory processes. Maternal BMI and male sex seem to be confounder for the expression of galectin-12 in the nuclear syncytiotrophoblast, but not in other parts of the investigated placental areas. Further investigations are necessary to verify the correlation between gestational diabetes mellitus and the expression of galectin-12 in the placenta and to further elucidate its distinct role

Steroidhormonrezeptoren sind positive Prognostikatoren für das Mammakarzinom – ist dies universell anwendbar oder abhängig von der Fokalität?

Ziel dieser Arbeit ist es, die prognostische Relevanz der etablierten Hormonrezeptoren - dem Östrogen- und Progesteronrezeptor - unter Berücksichtigung der Tumorfokalität neu zu evaluieren

EP3 Is an Independent Prognostic Marker Only for Unifocal Breast Cancer Cases

The aim of this study was to evaluate the prognostic impact of prostaglandin E2 receptor 3 (EP3) receptor expression might have on the two different breast cancer entities: multifocal/multicentric versus unifocal. As the prognosis determining aspects, we investigated the overall- and disease-free survival by uni-and multivariate analysis. To underline the study’s conclusion, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging system. A retrospective statistical analysis was performed on survival related events in a series of 289 sporadic breast cancer (BC) patients treated at the Department of Obstetrics and Gynecology at the Ludwig–Maximillian’s University in Munich between 2000 and 2002. The EP3 receptor expression was analyzed by immunohistochemistry and showed to have a significantly positive association with breast cancer prognosis for both entities, although with major differences. Patients with unifocal BC with EP3 receptor expression showed a significant improved overall survival, in contrast to the patient cohort with multifocal/multicentric BC. In this group, EP3 expression revealed its positive impact merely five years after initial diagnosis. Underlining the positive influence of EP3 as a positive prognosticator notably for unifocal breast cancer, only this patient cohort showed favorable outcomes in staging and grading. Especially EP3 expression in unifocal breast cancer was identified as an independent prognostic marker for the overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of EP3 in breast cancer and understand why markers linked to inflammation show different effects on prognosis and clinicopathological parameters on each focality type

Hormone Receptor Expression in Multicentric/Multifocal versus Unifocal Breast Cancer: Especially the VDR Determines the Outcome Related to Focality

The aim of this study was to evaluate the prognostic impact that hormone receptor (HR) expressions have on the two different breast cancer (BC) entities—multifocal versus unifocal BC. As the prognosis determining aspects, we investigated the overall survival (OS) and disease-free survival (DFS) by univariate and multivariate analysis. To underline the study’s conclusions, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging. A retrospective analysis was performed on survival-related events in a series of 320 breast cancer patients treated at the Department of Gynecology and Obstetrics at the Ludwig Maximillian University in Munich between 2000 and 2002. All three steroid receptors analyzed by immunohistochemistry, namely, the estrogen receptor (ER), the progesterone receptor (PR), and the vitamin D receptor (VDR), showed a significantly positive influence on the course of the disease, but only for the unifocal breast tumor patients. The prognosis of patients with multifocal breast cancer was either not affected by estrogen and/or progesterone receptor expression or even involved a worse etiopathology for the vitamin D receptor-positive patients. The estrogen receptor in unifocal breast cancer and the vitamin D receptor in multifocal breast cancer were especially identified as an independent prognostic marker for overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of the hormone receptors in breast cancer and understand why they have different effects on each focality type. Moreover, the studies for an adopted vitamin D supplementation due to breast cancer focality type must be enlarged to fully comprehend the remarkable and interesting role played by the vitamin D receptor