Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers

Brown, Kristy A.; Iyengar, Neil M.; Zhou, Xi Kathy; Gucalp, Ayca; Subbaramaiah, Kotha; Wang, Hanhan; Giri, Dilip; Morrow, Monica; Falcone, Domenick J.; Wendel, Nils K.; Winston, Lisle; Pollak, Michael; Dierickx, Anneloor; Hudis, Clifford A.; Dannenberg, Andrew J.

doi:10.1210/jc.2016-3606

Cited by 86 publications

(91 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adipocyte hypertrophy also enhances the production of pro‐inflammatory chemokines and cytokines, such as tumor necrosis factor‐α, interleukins, and leptin in human white adipose tissue, which may stimulate mutagenesis, tumor cell proliferation, survival, migration, angiogenesis, and stem cell survival . Moreover, a variety of molecules that are altered in association with excess body fat including the bioactive lipid prostaglandin E 2 (PGE 2 ) and leptin induce aromatase, the rate‐limiting enzyme for estrogen biosynthesis . Thus, systemic alterations, in combination with enhanced local estrogen production, are likely to contribute to the development of hormone receptor‐positive breast cancer …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a variety of molecules that are altered in association with excess body fat including the bioactive lipid prostaglandin E 2 (PGE 2 ) and leptin induce aromatase, the rate‐limiting enzyme for estrogen biosynthesis . Thus, systemic alterations, in combination with enhanced local estrogen production, are likely to contribute to the development of hormone receptor‐positive breast cancer …”

Section: Discussionmentioning

confidence: 99%

“…Specifically, in an obesogenic environment, adipocytes become enlarged. 41 These large adipocytes, which can be found in both breast adipose and visceral adipose tissue (VAT), are insulin-resistant and hyperlipolytic, and may therefore contribute to the elevated levels of insulin, glucose, and triglycerides, [41][42][43] as seen among women in the current study who had excess central adiposity. Chronic hyperglycemia is believed to stimulate tumor cell growth by causing epigenetic modifications.…”

Section: Discussionmentioning

confidence: 99%

“…44,45 Moreover, a variety of molecules that are altered in association with excess body fat including the bioactive lipid prostaglandin E 2 (PGE 2 ) and leptin induce aromatase, the rate-limiting enzyme for estrogen biosynthesis. 2,43 Thus, systemic alterations, in combination with enhanced local estrogen production, are likely to contribute to the development of hormone receptor-positive breast cancer. 2,43 Lean body mass is thought to exert anti-carcinogenic benefits by inhibiting cancer-associated processes such as insulin resistance, chronic inflammation, and dysregulated lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

The association between DXA‐derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk. Methods Cox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years. Results Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses. Conclusion These findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The association between DXA‐derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…[3] The increased risk of developing HR-positive breast cancer in obese postmenopausal women has been attributed, in part, to increased expression of aromatase in breast adipose tissue. [4–6]…”

Section: Introductionmentioning

confidence: 99%

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Gucalp

Zhou

Cook

et al. 2018

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer (BC) and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III BC, DCIS/LCIS, Paget’s disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1000mg by mouth twice daily) reduced breast tissue levels of TNF-α. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL-1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 – November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P<0.001) but not placebo. Treatment with DHA did not alter levels of TNF-α (P=0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared to placebo.

show abstract

Associations of reproductive factors with breast cancer prognosis and the modifying effects of menopausal status

Zhang

Wang

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

Reproductive factors associated with breast cancer risk may also affect the prognosis. This study aimed to evaluate the associations of multiple reproductive factors with breast cancer prognosis and the modifying effects of menopausal status. We obtained data from 3805 breast cancer patients recruited between October 2008 and June 2016 in Guangzhou. The subjects were followed up until 30 June 2018. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using multivariate Cox models to estimate the associations. It was found that there were U‐shaped patterns for the associations of age at first birth and durations from first/last birth to diagnosis with breast cancer prognosis. The adverse effects of old age at first birth [>30 years vs 23‐30 years, HR (95% CI): 1.59 (1.01‐2.50)] and long intervals from first [≥20 years vs 10‐19 years, HR (95% CI): 1.55 (1.07‐2.27)] or last [≥20 years vs 10‐19 years, HR (95% CI): 1.63 (1.08‐2.46)] birth to diagnosis on progression‐free survival (PFS) were significantly more pronounced among premenopausal women. Additionally, long interval (>5 years) between first and second birth was associated with a better PFS [HR (95% CI): 0.64 (0.42‐0.97)]. These results suggested that age at first birth, durations from first/last birth to diagnosis, and intervals between first and second birth should be taken into account when following the patients and assessing the prognosis of breast cancer, particularly for premenopausal patients. These findings would also have implications for further insight into the mechanisms of breast cancer development.

show abstract

Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers

Abstract: Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

Cited by 86 publications

References 44 publications

The association between DXA‐derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative

The association between DXA‐derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Associations of reproductive factors with breast cancer prognosis and the modifying effects of menopausal status

Contact Info

Product

Resources

About