Obesity enhances nongenomic estrogen receptor crosstalk with the PI3K/Akt and MAPK pathways to promote in vitro measures of breast cancer progression

Bowers, Laura W.; Cavazos, David; Maximo, Ilane X F; Brenner, Andrew; Hursting, Stephen D.; deGraffenried, Linda A.

doi:10.1186/bcr3453

Cited by 37 publications

(43 citation statements)

References 55 publications

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“…In contrast, the lack of difference in serum estradiol levels by BMI does not agree with the literature, as researchers have generally found that obese postmenopausal women have higher estradiol levels (39)(40)(41). However, of the 25 women that provided the sera for this study, 9 obese patients and 1 normal-weight patient were receiving an aromatase inhibitor (21), which may have masked any difference in estradiol levels between the groups.…”

Section: Discussioncontrasting

confidence: 52%

“…Consequently, this difference in macrophage COX-2 expression and PGE2 production may be because of elevated levels of these free fatty acids in the obese patient sera. There is also some evidence that the inflammatory cytokines IL6 and TNFa, found in higher concentrations in our obese patient serum samples (21), can induce COX-2 expression (27,35,36). This suggests that more than one mechanism may be responsible for the obesity-associated upregulation of macrophage COX-2 expression and PGE2 production seen in this study.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, we utilized an in vitro model in which cultured cells were exposed to pooled sera samples from obese or normal-weight postmenopausal patients with breast cancer to mimic the tumor microenvironment of obese versus normal-weight women. The characteristics of the serum donors, including serum concentrations of various cytokines, adipokines, and growth factors, have been previously described (21). Following a 1 hour exposure to OB sera, COX-2 expression in cultured macrophages was a modest 24% higher than cells exposed to N sera (Fig.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…The ERE luciferase assay was performed as described previously (21), with the MCF-7 and T47D cells exposed for 48 hours to the macrophage/preadipocyte coculture CM supplemented with 2% CS-FBS. Relative ERa activity was calculated by dividing the fluorescence value (standardized to renilla) from cells grown in each experimental condition by that from cells grown in CM generated with exposure to sera from patients of normal weight followed by incubation in SFM plus testosterone.…”

Section: Ere Luciferase Assaymentioning

confidence: 99%

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NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions

et al. 2014

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Obesity is associated with a worse breast cancer prognosis and elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the proinflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. This study demonstrates that daily use of a nonsteroidal anti-inflammatory drug (NSAID), which inhibits COX-2 activity, is associated with reduced estrogen receptor a (ERa)-positive breast cancer recurrence in obese and overweight women. Retrospective review of data from ERa-positive patients with an average body mass index of >30 revealed that NSAID users had a 52% lower recurrence rate and a 28-month delay in time to recurrence. To examine the mechanisms that may be mediating this effect, we conducted in vitro studies that utilized sera from obese and normal-weight patients with breast cancer. Exposure to sera from obese patients stimulated greater macrophage COX-2 expression and PGE2 production. This was correlated with enhanced preadipocyte aromatase expression following incubation in conditioned media (CM) collected from the obese-patient, sera-exposed macrophages, an effect neutralized by COX-2 inhibition with celecoxib. In addition, CM from macrophage/preadipocyte cocultures exposed to sera from obese patients stimulated greater breast cancer cell ERa activity, proliferation, and migration compared with sera from normal-weight patients, and these differences were eliminated or reduced by the addition of an aromatase inhibitor during CM generation. Prospective studies designed to examine the clinical benefit of NSAID use in obese patients with breast cancer are warranted. Cancer Res; 74(16); 4446-57. Ó2014 AACR.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Patient Characteristicsmentioning

confidence: 99%

Section: Ere Luciferase Assaymentioning

confidence: 99%

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NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions

et al. 2014

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“…In addition, our results align with the finding in patients that adipocytes located near tumor cells up-regulate IL-6 production (27, 42, 55). The link between IL-6 and obesity is well-established (60–62). In addition, transcriptomic analysis revealed marked up-regulation of IL-6 inflammatory pathway in the tumors of BC patients with obesity in comparison to those without obesity (63).…”

Section: Discussionmentioning

confidence: 99%

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

et al. 2018

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Anti–vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy’s lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.

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Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

Nagaprashantha

Adhikari

Singhal

et al. 2017

Intl Journal of Cancer

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Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC. Breast tumors modulate ERα/ERβ ratio, upregulate proliferative pathways driven by ERα and HER2 with a parallel loss and/or downregulation of tumor suppressors such as TP53 and PTEN which together impact the efficacy of therapeutic strategies and frequently lead to emergence of drug resistance. Natural phytochemicals modulate oxidative stress, leptin, integrin, HER2, MAPK, ERK, Wnt/β-catenin and NFκB signaling along with regulating ERα and ERβ, thereby presenting unique opportunities for both primary and combinatorial interventions in BC. In this regard, this article focuses on critical analyses of the evidence from multiple studies on the efficacy of natural phytochemicals in BC. In addition, areas in which the combinations of such effective natural phytochemicals with approved and/or developing anticancer agents can be translationally beneficial are discussed to derive evidence-based inference for addressing challenges in BC control and therapy.

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Obesity enhances nongenomic estrogen receptor crosstalk with the PI3K/Akt and MAPK pathways to promote in vitro measures of breast cancer progression

Cited by 37 publications

References 55 publications

NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions

NSAID Use Reduces Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin–Aromatase Interactions

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

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