Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review

Ioannides, Sally J.; Barlow, Phillip; Elwood, J. Mark; Porter, D.

doi:10.1007/s10549-014-3091-7

Cited by 61 publications

(49 citation statements)

References 32 publications

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“…Moreover, obesity is a factor that has been associated with both increased risk and poor breast cancer prognosis due to possible local adipose inflammation and increased levels of inflammatory and protumorigenic factors (48). Aromatase inhibitors are currently first-line therapy for hormone receptor-positive postmenopausal breast cancer (49); however, some studies have suggested that aromatase inhibitors may be less effective in obese women and these women may have a poorer prognosis due to greater peripheral aromatase activity and plasma estrogen levels (50).…”

Section: Discussionmentioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E 2 , inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. Cancer Res; 75(23); 5001-7. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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“…Several clinical trials have revealed that many pathways could be targeted to specifically inhibit aromatase within the breast. For example, through targeting aromatase inhibitors (AIs), clinical treatment may inhibit the activity of aromatase enzymes and prevent estrogen production 211. Although targeted therapy has achieved promising results, it also has certain side effects.…”

Section: Adipose Cellsmentioning

confidence: 99%

Role of tumor microenvironment in tumorigenesis

et al. 2017

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Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

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“…Some controversy exists regarding the effect of obesity on breast cancer risk before menopause, but studies have definitively shown elevated risk in obese, postmenopausal women (reviewed in [4]), particularly for estrogen receptor (ER) positive disease [2, 5]. Obese women typically present with larger tumors and more frequent lymph node involvement [6], and are less likely to benefit from traditional anti-hormonal therapies, such as tamoxifen or aromatase inhibitors [7]. Further, regardless of menopausal status, obese women with breast cancer are more likely to die from the disease compared to their lean counterparts [2].…”

Section: Introductionmentioning

confidence: 99%

The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer

et al. 2017

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The androgen receptor (AR) has context-dependent roles in breast cancer growth and progression. Overall, high tumor AR levels predict a favorable patient outcome, but several studies have established a tumor promotional role for AR, particularly in supporting the growth of estrogen receptor positive (ER-positive) breast cancers after endocrine therapy. Our previous studies have demonstrated that obesity promotes mammary tumor progression after ovariectomy (OVX) in a rat model of postmenopausal breast cancer. Here, we investigated a potential role for AR in obesity-associated post-OVX mammary tumor progression after ovarian estrogen loss. In this model, we found that obese but not lean rats had nuclear localized AR in tumors that progressed three weeks after OVX, compared to those that regressed. AR nuclear localization is consistent with activation of AR-dependent transcription. Longer-term studies (8 weeks post-OVX) showed that AR nuclear localization and expression were maintained in tumors that had progressed, but AR expression was nearly lost in tumors that were regressing. The anti-androgen Enzalutamide effectively blocked tumor progression in obese rats by promoting tumor necrosis, and also prevented the formation of new tumors after OVX. Neither circulating nor mammary adipose tissue levels of the AR ligand testosterone were elevated in obese compared to lean rats; however, IL-6, which we previously reported to be higher in plasma from obese versus lean rats, sensitized breast cancer cells to low levels of testosterone. Our study demonstrates that, in the context of obesity, AR plays a role in driving ER-positive mammary tumor progression in an environment of low estrogen availability, and that circulating factors unique to the obese host, including IL-6, may influence how cancer cells respond to steroid hormones.

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Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review

Cited by 61 publications

References 32 publications

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

Role of tumor microenvironment in tumorigenesis

The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer

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