Inflammation In Breast Cancer Research Articles

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer.

We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX-like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin-4. In addition, LOX was associated with cluster of differentiation 8+ T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF-negative compared with that in the FF-positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer.

Abstract P6-05-05: The expression of lysyl oxidase and fibrotic focus is related to inflammation in breast cancer

Abstract Background: Lysyl oxidase (LOX) is an extracellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. Our hypothesis is that LOX contributes to the formation of a fibrotic focus (FF), which is related to inflammation in breast carcinogenesis. In this study, we analyzed the association between the expression LOXs and FF, and investigated prognostic significance in breast cancer. Methods: Tissue microarrarys were constructed from the specimens of 444 patients with primary invasive breast cancer. Immunohistochemical staining for LOX, LOXlike (LOXL)-, LOXL-2 and LOXL-3 was performed. The status of FF within the tumor was assessed. The number of CD4+ T cells, CD8+ T cells, CD68+ macrophages was counted, and intratumoral and peritumoral lymphocyte infiltration were evaluated. The clinicopathologic characteristics of the patients were analyzed. Result: The percentage of positive FF was 39.2% and positive rate of LOX expression was 50% in primary breast cancer tissues. FF was found to be significantly associated with intratumoral and peritumoral inflammation, lymph node metastasis, high histologic grade, larger tumor size. LOX was associated with intratumoral and peritumoral inflammation, CD8+ T cells and menopausal status. LOXL-3 was significantly associated with positive expression of ER and PR, and molecular subtype. Conclusions: FF and the expression of LOX were associated with inflammation in breast cancer in this study. Our results suggest that LOXs may contribute to the formation of a FF indirectly in relation with inflammation in breast cancer. Further studies are needed to clarify the role of LOXs, FF and inflammation in tumorigenesis and prognostic value of them in breast cancer. Citation Format: Park SH, Jeong YJ, Bong JG, Oh HK. The expression of lysyl oxidase and fibrotic focus is related to inflammation in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-05-05.

The Interaction of Obesity and Inflammation in Breast Cancer

Obesity and overweight have closely considered with several chronic diseases. Evidence of this field has demonstrated that significantly impact on the multiple cancers progression, such as breast cancer, prostate cancer, hepatocellular carcinoma, pancreatic cancer and cervical cancer. Epidemiological studies have shown that there is about 20% of cancer related to obesity, which were affected by lifestyle including dietary behavior and physical activity. Based on these findings, obesity is considered as one of most harmful factors for the breast cancer in women, especially after menopause. Many hypotheses have been proposed to explain how obesity contributes to breast cancer development. The inflammatory cytokines produced from adipocytes is one of main reason triggers tumor microenvironment and tumor progression. Better understanding the association between adipocytes and inflammation implanting breast tumor development could apply to develop new alternative methods for prevention/cure. In this review, we summarize the concept and evidence associated to interaction of obesity-driven changes and inflammation in breast cancer microenvironment.

The Interaction of Obesity and Inflammation in Breast Cancer

The Interaction of Obesity and Inflammation in Breast Cancer

The immune system and inflammation in breast cancer

During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.

Abstract B103: Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis

Abstract Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrated that CAFs also mediate tumor-enhancing inflammation: CAFs isolated from pre-neoplastic and tumor tissue expressed a pro-inflammatory gene signature and functioned to recruit macrophages and enhance tumor angiogenesis in a mouse model of squamous carcinoma. Moreover, we demonstrated that pro-inflammatory signaling by CAFs is operative also in mouse and human breast carcinogenesis. Although breast cancer is one of the major tumor types where CAFs were shown to be tumor promoting, there is no detailed analysis of CAF characteristics and function in correlation with tumor progression. We therefore set out to characterize the dynamic changes in CAFs during progression of mammary carcinogenesis, in a transgenic mouse model of human breast cancer, the MMTV-PyMT mice. We show that normal mammary fibroblasts can be “educated” by mammary carcinoma cells to become activated, pro-inflammatory CAFs. Furthermore, transcriptome profiling of fibroblasts isolated from normal mammary glands, or from mammary glands of transgenic mice at defined tumorigenic stages (hyperplasia, early carcinoma, invasive adenocarcinoma) revealed distinct CAF gene expression signatures that correspond to different tumor stages, with only partial overlap between the stages, suggesting co-evolution of the microenvironment with tumorigenic progression. Interestingly, the gene signature of fibroblasts isolated from hyperplastic lesions is inverse to that in CAFs from neoplastic stages, and has a putative growth inhibitory phenotype, while CAFs from early and late carcinoma express pro-inflammatory and tumor promoting gene signatures. Elucidating the molecular mechanisms by which CAFs mediate cancer-related inflammation in breast cancer will greatly increase our understanding of stromal pathways that contribute to tumorigenesis, in an effort to identify novel stromal molecular targets for combinatorial therapeutic approaches to combat breast cancer progression. Citation Format: Yoray Sharon, Yael Raz1,2, Lina Alon, Neta Erez. Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B103.

HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis

HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers.

The role of inflammation in breast cancer and prostate cancer

Inflammatory conditions increase the risk of cancer. Strong evidences showed that inflammation contributes to breast cancer and prostate cancer in different ways such as inflammation-induced DNA or RNA damage, overexpression cytokines, chemokines etc. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Some possible mechanisms by which inflammation can contribute to carcinogenesis have been found. These mechanisms by which inflammation contributes to cancer give broader views of cancer development. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Metabolic Syndrome, Insulin Resistance, and Inflammation in Breast Cancer: Impact on Prognosis and Adjuvant Interventions

The metabolic syndrome, a clinical syndrome that includes central obesity, dyslipidemia, hypertension and glucose intolerance, has been associated with diabetes and cardiovascular disease. Recent evidence links it to breast cancer risk and outcome and suggests that existing adjuvant therapies may exacerbate the syndrome and have reduced efficacy when the syndrome is present. Potential mediators of effects of the syndrome on cancer include insulin/insulin-like growth factor, adipocytokines such as leptin, and markers of inflammation such as interleukins, C-reactive protein, and serum amyloid A. Growing epidemiologic, clinical, and preclinical evidence suggests insulin may be a key mediator. Potential interventions include changes in lifestyle (weight loss, increased physical activity) or pharmacologic approaches. Metformin, a drug commonly used to treat diabetes that reduces the hyperinsulinemia and hyperglycemia associated with the metabolic syndrome, shows promise in epidemiologic, preclinical, and clinical work. Interventions trials involving metformin are underway, including a large adjuvant study by the National Cancer Institute of Canada known as NCIC CTG MA.32.

The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast

The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. Results: Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44–0.74] on multivariate analysis. Typical and atypical medullary carcinomas ( n = 132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation ( P < 0.0001 and P = 0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour.

Freund's vaccine adjuvant promotes Her2/Neu breast cancer

BackgroundInflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis in a rat model in which cancer is induced by the neu oncogene.MethodsThe effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a neu-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed.ResultsRats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis.ConclusionOur data suggests that systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer.

Tumor Necrosis Factor-α Stimulates Focal Adhesion Kinase Activity Required for Mitogen-activated Kinase-associated Interleukin 6 Expression

Tumor Necrosis Factor-α Stimulates Focal Adhesion Kinase Activity Required for Mitogen-activated Kinase-associated Interleukin 6 Expression

Different patterns of inflammation and prognosis in invasive carcinoma of the breast

Inflammation in carcinoma of the breast may represent an immune response to the tumour, but there is evidence that this response is impaired. Inflammation may also stimulate tumour growth by releasing proteolytic enzymes and angiogenic factors. Prognostic studies have produced conflicting results, but most investigators have not evaluated the different patterns of inflammation. The aim of this study was to test the hypothesis that moderate or marked diffuse inflammation is associated with a better prognosis. We also tested the 'danger model', which suggests that necrosis is necessary for an effective immune response. On multivariate analysis of women with stage 1 and 2 tumours (n = 679, median follow-up of 9.8 years), survival was independently associated with diffuse inflammation (relative risk 0.43, 95% confidence interval 0.24, 0.77, P =0.005) in addition to histological grade, axillary lymph node status, tumour size and oestrogen receptor status. The presence or absence of tumour necrosis did not have a clear effect on the relationship between survival and diffuse inflammation. Moderate or marked diffuse inflammation in breast cancer is associated with a better prognosis, suggesting that the immune effects of the inflammation predominate over the protumour effects.