Obesity and Postmenopausal Hormone Receptor-positive Breast Cancer: Epidemiology and Mechanisms

Zuo, Qianying; Band, Shoham; Kesavadas, Mrinali P.; Madak-Erdoğan, Zeynep

doi:10.1210/endocr/bqab195

Cited by 19 publications

(13 citation statements)

References 127 publications

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“…Histone 3 displays altered acetylation at lysine 4, 9, and 27 in breast cancer cells that fail to respond to ER antagonists (65)(66)(67). Systemic metabolic changes impact hormone-dependent cancer cell metabolism (41,68) and composition of histone marks (39,69), and response to therapies (19,41). Our findings suggest an altered ERα activity in MBC cells residing in the liver microenvironment, and a role for metabolic and epigenetic enzymes to interact with ER in a Fulv-dependent manner to locally change epigenetic marks, which would lead to altered response to ERα antagonists.…”

Section: Discussionmentioning

confidence: 99%

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Zuo

Mogol

Liu

et al. 2022

Molecular Cancer Research

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Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in the liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. Implications: These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

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Section: Discussionmentioning

confidence: 99%

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Zuo

Mogol

Liu

et al. 2022

Molecular Cancer Research

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“…This study had two aims. The first one was to examine the efficacy of exercise in producing total and abdominal fat loss in postmenopausal women and provide information that could alleviate some of the health risks associated with overweight and obesity in general [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and with obesity in postmenopausal women in particular [ 16 , 17 , 18 , 19 ], given the weight gain and redistribution of body fat from peripheral to more deleterious central sites associated with menopause [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 54 ]. We focused on the speed of movement as the likely variable to affect both the rate of total and SC and VF fat loss and the retention of LBM, and also because it was shown to be required for the suppression of bone mineral loss in the same subjects being analyzed in the present study [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Between 1960 and 2020, obesity in women and men in the U.S. increased more than threefold, from 13.4 to 41.9% [ 1 , 2 ]. Overweight, defined as body mass index (BMI) of between 25 and 30 kg/m 2 , and obesity, as BMI above 30 kg/m 2 , often leads to pathologies such as diabetes, atherosclerotic vascular disease that may precipitate stroke, heart attack, pulmonary thromboembolism, respiratory failure, and cancer [ 3 , 4 , 5 ]. Mortality risk rises in parallel with increases in obesity [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Walking Speed on Total and Regional Body Fat in Healthy Postmenopausal Women

New

Borer

2022

Nutrients

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Introduction: This study had two aims: (1) To confirm the efficacy of exercise speed and impulse (session duration at a given speed) to produce total and abdominal fat loss in postmenopausal women, and (2) compare the exercise speed and impulse necessary for the stimulation of fat loss to the suppression of bone mineral loss. Of special interest was to compare these parameters of exercise on fat loss in the same study and with the same subjects where they were found to suppress bone mineral loss. We hypothesized that (1) more total fat will be lost with slow walking and a longer impulse than with fast speed and shorter impulse, and (2) more abdominal subcutaneous (SC) and visceral fat (VF) will be lost with fast walking speed. Materials and Methods: Fat loss and suppression of bone mineral loss were measured in the same 25 subjects after 15 weeks, and fat measurements were also taken after 30 weeks in 16 residual subjects. Study parameters were walking a 4.8 km distance 4 days/week at either 6.6 km/h (120% of ventilatory threshold (VT)) or at 5.5 km/h (101.6% of VT) and expending 300 kcal/session. Body composition (fat and lean body mass, LBM) was measured with dual-energy X-ray absorptiometry (DXA) and anthropometric methods. Results: Slow walkers in the residual group progressively lost a significant percent of total body fat over 30 weeks while no such loss occurred after 15 weeks in fast walkers in either group, supporting hypothesis 1. However, the 20% higher starting body fat in 16 residual slow relative to fast subjects suggests that exercise fat loss is greater in overweight than in lean subjects. In fast walkers, fat loss occurred after 30 weeks of training. Hypothesis 2 was not supported as both speeds led to equal VF loss in 30-week group as estimated by waist circumference (CF) confirming that VF responds to the magnitude of energy expenditure and not the walking speed. Conclusions: Total body fat is lost through walking at all speeds, but the change is more rapid, clear, and initially greater with slow walking in overweight subjects. A longer exercise impulse at a lower speed in our study initially produced greater total fat loss than a shorter one with fast walking speed. This was reversed in comparison to how the same exercise in the same subjects suppressed bone mineral loss. Data from other studies indicate that longer impulses may promote greater fat loss at both slow and high exercise speeds, and our study providing only a 4.8 km walking distance may have limited the walking impulse and the magnitude of fat loss. Increased exercise energy expenditure at either walking speed produces equivalent declines in visceral fat in postmenopausal women, and with sufficiently long impulses, should reduce disabilities associated with central obesity.

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“…Moreover, hyperthyroidism is often associated with adverse survival outcomes after cancer diagnosis. Conversely, primary hypothyroidism is associated with reduced breast cancer risk and more indolent cancers, as suggested by the smaller tumor size and lower rates of pathologic lymph node involvement [28]. Despite this reduced risk, hypothyroidism is associated with obesity, which is a risk factor for the development of ER-positive breast cancers [29].…”

Section: The Hypothalamic-pituitary-thyroid Axis and Systemic Effects...mentioning

confidence: 99%

The TSH/Thyroid Hormones Axis and Breast Cancer

Voutsadakis

2022

JCM

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Breast cancer, the most prevalent female carcinoma, is characterized by the expression of steroid nuclear receptors in a subset of cases. The most important nuclear receptor with prognostic and therapeutic implications is the Estrogen Receptor (ER), which is expressed in about three out of four breast cancers. The Progesterone Receptor (PR) and the Androgen Receptor (AR) are also commonly expressed. Moreover, non-steroid nuclear receptors, including the vitamin D receptor (VDR) and the thyroid receptors (TRs), are also present in breast cancers and have pathophysiologic implications. Circulating thyroid hormones may influence breast cancer risk and breast cancer cell survival, through ligating their canonical receptors TRα and TRβ but also through additional membrane receptors that are expressed in breast cancer. The expression of TR subtypes and their respective isotypes have diverse effects in breast cancers through co-operation with ER and influence on other cancer-associated pathways. Other components of the TSH/thyroid hormone axis, such as TSH and selenoiodinase enzymes, have putative effects in breast cancer pathophysiology. This paper reviews the pathophysiologic and prognostic implications of the thyroid axis in breast cancer and provides a brief therapeutic perspective.

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Obesity and Postmenopausal Hormone Receptor-positive Breast Cancer: Epidemiology and Mechanisms

Cited by 19 publications

References 127 publications

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Effects of Walking Speed on Total and Regional Body Fat in Healthy Postmenopausal Women

The TSH/Thyroid Hormones Axis and Breast Cancer

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