Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Carter, Jodi M.; Hoskin, Tanya L.; Pena, Monica-Cătălina; Brahmbhatt, Rushin D.; Winham, Stacey J.; Frost, Marlene H.; Stallings-Mann, Melody; Radisky, Derek C.; Knutson, Keith L.; Visscher, Daniel W.; Degnim, Amy C.

doi:10.1158/1940-6207.capr-17-0245

Cited by 56 publications

(59 citation statements)

References 33 publications

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“…Consistent with these observations, Carter et al recently reported that high levels of breast white adipose inflammation were associated with increased breast cancer risk. 36 …”

Section: Discussionmentioning

confidence: 99%

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index

et al. 2019

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Importance: Obesity is associated with increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. It is unknown whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI). Objective: To investigate the association between body fat and breast cancer risk in normal BMI women. Design: This secondary analysis of the Women’s Health Initiative (WHI) cohort was restricted to participants with BMI 18.5 to <25.0 kg/m2. Setting: Women ages 50 to 79 years were enrolled from 1993 to 1998. Body fat was measured by dual energy X-ray absorptiometry (DXA) at 3 designated centers. Participants: 3,460 postmenopausal women with normal BMI who had DXA measures were included. At a median follow-up of 16 years, 182 incident breast cancers had been ascertained; 146 were ER-positive. Main Outcomes and Measures: DXA-derived body fat levels were measured at baseline and years 1, 3, 6, and 9. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analytes were measured in subsets of participants. Results: Multivariable-adjusted hazard ratios (HRs) for risk of invasive breast cancer were 1.89 (95% CI 1.21 to 2.95) and 1.88 (95% CI 1.18 to 2.98) in the uppermost versus lowest quartiles of whole body fat and trunk fat mass, respectively. The corresponding adjusted HRs for ER-positive breast cancer were 2.21 (95% CI 1.23 to 3.67) and 1.98 (95% CI 1.18 to 3.31), respectively. Similar positive associations were observed when accounting for serial DXA measurements in time-dependent covariate analyses for ER-positive breast cancer. Circulating insulin, C-reactive protein, interleukin-6, leptin and triglycerides were higher, while HDL-cholesterol and sex hormone binding globulin were lower in the uppermost versus lowest quartiles of trunk fat mass. Conclusions and Relevance: In normal BMI postmenopausal women, relatively high body fat was associated with elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.

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“…Consistent with these observations, Carter et al recently reported that high levels of breast white adipose inflammation were associated with increased breast cancer risk. 36 …”

Section: Discussionmentioning

confidence: 99%

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index

et al. 2019

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“…In engineered mice, reduced levels of SIRT1 in adipose tissue have been associated with macrophage influx and the development of adipose inflammation (34,35). A similar low-grade inflammatory process was recently linked to the pathogenesis of human breast cancer (36,37). Taken together, the observed reduction in SIRT1 in the breast tissue of obese women may be causally linked to both subclinical inflammation and elevated aromatase expression, contributing to the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women.…”

Section: Figure 8 Atf3 Is Important For Pge 2 -Mediated Down-regulatmentioning

confidence: 94%

Prostaglandin E2 down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity–breast cancer connection

Subbaramaiah

Iyengar

Morrow

et al. 2019

Journal of Biological Chemistry

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Obesity increases the risk of hormone receptor-positive breast cancer in postmenopausal women. Levels of aromatase, the ratelimiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E 2 (PGE 2 ) and hypoxia-inducible factor 1␣ (HIF-1␣) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1␣. Here, we sought to determine whether SIRT1 also plays a role in regulating aromatase expression. We demonstrate that reduced SIRT1 levels are associated with elevated levels of acetyl-HIF-1␣, HIF-1␣, and aromatase in breast tissue of obese compared with lean women. To determine whether these changes were functionally linked, ASCs were utilized. In ASCs, treatment with PGE 2 , which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl-HIF-1␣ and HIF-1␣ levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE 2 -mediated induction of acetyl-HIF-1␣, HIF-1␣, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1␣, blocked PGE 2 -mediated increases in acetyl-HIF-1␣, HIF-1␣, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1␣ and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE 2 acted via prostaglandin E2 receptor 2 (EP 2 ) and EP 4 to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the SIRT1 promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1mediated deacetylation of HIF-1␣ contributes to the elevated levels of aromatase in breast tissues of obese women. . 3 The abbreviations used are: ER, estrogen receptor; CRE, cyclic AMP-response element; CREB, CRE-binding protein; HIF-1␣, hypoxia inducible factor-1␣; PGE 2 , prostaglandin E 2 ; ASC, adipose stromal cell; SIRT1, sirtuin 1; BMI, body mass index; PCAF, p300/CBP-associated factor; PKA, protein kinase A; ATF3, activating transcription factor 3; EP, prostaglandin E2 receptor; HRE, hypoxia-responsive element; FPKM, fragments per kilobase per million.

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“…A distinct feature of low-grade inflammation in AT is the formation of crown-like structures (CLS) which are syncytial arrangements comprised of encircled necrotic/damaged adipocytes with macrophages. The presence of CLS is associated with elevated levels of inflammatory mediators, mainly TNFα and prostaglandin E2 [53]. Investigations have revealed that these macrophages may resorb the lipid remnants of encircled dead adipocytes and also contribute to inflammation [54].…”

Section: Role Of Monocytes and Macrophage Within Atmentioning

confidence: 99%

Crosstalk Between Mast Cells and Adipocytes in Physiologic and Pathologic Conditions

Komi

Shafaghat

Christian

2020

Clinic Rev Allerg Immunol

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Excessive fatty acids and glucose uptake support the infiltration of adipose tissue (AT) by a variety of immune cells including neutrophils, pro-inflammatory M1 macrophages, and mast cells (MCs). These cells promote inflammation by releasing proinflammatory mediators. The involvement of MCs in AT biology is supported by their accumulation in the AT of obese individuals along with significantly higher serum levels of MC-derived tryptase. AT-resident MCs under the influence of locally derived adipokines such as leptin become activated and release pro-inflammatory cytokines including TNFα that worsens the inflammatory state. MCs support angiogenesis in AT by releasing chymase and inducing preadipocyte differentiation and also the proliferation of adipocytes through 15-deoxy-delta PGJ2/PPARγ interaction. Additionally, they contribute to the remodeling of the AT extracellular matrix (ECM) and play a role in the recruitment and activation of leukocytes. MC degranulation has been linked to brown adipocyte activation, and evidence indicates an important link between MCs and the appearance of BRITE/beige adipocytes in white AT. Cell crosstalk between MCs and AT-resident cells, mainly adipocytes and immune cells, shows that these cells play a critical role in the regulation of AT homeostasis and inflammation.

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Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Cited by 56 publications

References 33 publications

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index

Prostaglandin E2 down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity–breast cancer connection

Crosstalk Between Mast Cells and Adipocytes in Physiologic and Pathologic Conditions

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