Breast Density and Estradiol Are Major Determinants for Soluble TNF-TNF-R Proteins in vivo in Human Breast Tissue

Abstract

High mammographic density and exposure to sex steroids are independent risk factors for breast cancer by yet unknown mechanisms. Inflammation is one hallmark of cancer and the tumor necrosis factor family of proteins (TNFSFs) and receptors (TNFRSFs) are key determinants of tissue inflammation. The relationship between TNFSFs/TNFRSFs and breast tissue density or local breast estradiol levels is unknown. We investigated whether TNFSFs and soluble TNFRSFs (sTNFRSFs) are dysregulated in vivo in human breast cancer and dense breast tissue of postmenopausal women. We explored TNFSF/TNFRSF correlations with breast density and estradiol, both locally in the breast and in abdominal subcutaneous (s.c.) fat as a measure of systemic effects. Microdialysis was used for local sampling of in vivo proteins and estradiol in a total of 73 women; 12 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 healthy premenopausal women. Breast density was determined as lean tissue fraction (LTF) using magnetic resonance imaging. Microdialysis was also performed in estrogen receptor (ER) positive breast cancer in mice treated with the pure anti-estrogen fulvestrant and tumor tissue was subjected to immunohistochemistry. 23 members of the TNFSF/sTNFRSF families were quantified using proximity extension assay.Our data revealed upregulation of TNFSF10, 13 and 13B, TNFRSF6, 6B, 9, 11A, 11B, 13B, 14, and 19, and TNFR-1 and -2 in ER+ breast cancer in women. In dense breast tissue TNFSF10, 13, and 14, TNFRSF3, 6, 9, 10B, 13B, 14, 19, and TNFR-1 and -2 were upregulated. Certain TNFSFs/TNFRSFs were increased in premenopausal breasts relative to postmenopausal breasts. Furthermore, estradiol correlated with most of the TNFSF/sTNFRSF members, though LTF only correlated with some of the proteins. Several of these associations were breast tissue-specific, as very few correlated with estradiol in abdominal s.c. fat. Estrogen dependent regulations of TNFSF2 (TNF-α) and TNF-R2 were corroborated in ER+ breast cancer in mice. Taken together, our data indicate TNFSFs/sTNFRSFs may represent potential targetable pathways for treatment of breast cancer patients and in prevention of breast cancer development in women with dense breasts.

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients Introduction

“…We also explored the relationship between different risk groups and immune checkpoints. In the high-risk group, the expression of tumor necrosis factor superfamily receptor/superfamily (TNFSF/TNFRSF) [49,50] was higher than that in the low-risk group. While the expression of CD40, HAVCR2, LAG3, and PDCD1LG2 is more in the low-risk group.…”

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients

“…We also explored the relationship between different risk groups and immune checkpoints. In the high-risk group, the expression of tumor necrosis factor superfamily receptor/superfamily (TNFSF/TNFRSF) [ 49 , 50 ] was higher than that in the low-risk group. At the same time, the expression of CD40, HAVCR2, LAG3, and PDCD1LG2 is more in the low-risk group.…”

Breast density and estradiol are associated with distinct different expression patterns of metabolic proteins in normal human breast tissue in vivo

“…The women were subjected to magnetic resonance imaging (MRI) ( 18 , 19 ). On the MRI lean tissue fraction (LTF), as a continuous measure of breast density, was calculated in a volume selection of 20 x 20 x 20 mm in the upper lateral quadrant of the left breast, as previously described ( 19 , 20 ). In brief, 1.5 T Achieva MR scanner (Philips Healthcare, Best, Netherlands) using a dual breast seven-element breast coil was used.…”