Obesity promotes the expansion of metastasis-initiating cells in breast cancer

Abstract

BackgroundObesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood.MethodsTo elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients.ResultsOur results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation.ConclusionsThese data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site.Graphical abstractEffects of postmenopausal obesity on primary breast cancer tumoursᅟElectronic supplementary materialThe online version of this article (10.1186/s13058-018-1029-4) contains supplementary material, which is available to authorized users.

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Additionally, Cowen et al (39) reported a higher body weight in female MMTV-PyMT mice on a HFD (35.7% energy from fat) compared to mice on a LFD (10% energy from fat), even after adjusting for tumor weight and tumor volume. Others reported that DIO promotes tumor growth, progression, and metastasis in animal models (40,41), specifically in breast cancer (16,17,33). In addition, poor treatment outcomes are also reported in overweight and obese breast cancer patients evident by larger tumor sizes and poor clinical outcomes (7,18,42,43) especially those treated with doxorubicin (42,44).…”

“…Recently, findings from cell culture and animal models identified obesity as a main contributing factor in the underlying pathophysiology implicated in the development of breast cancer chemotherapeutic drug resistance (16,17). Patients suffering from obesity and breast cancer presented with poor clinical outcomes when treated with first line adjuvant regimens such as doxorubicin (18,19).…”

EO771, is it a well‐characterized cell line for mouse mammary cancer model? Limit and uncertainty

“…Despite their isolation in the late 1940s, characterization of hormonal receptors and classification of EO771 line remains controversial. Indeed, its classification diverges according to the authors, which is considered as triple negative in 10 publications 6,12,16‐23 and as ERα+ in 19 publications 13,24‐41 . Some authors prefer to mention the unclear status of this lineage 42,43 .…”

Association of Omentin-1 with Oxidative Stress and Clinical Significances in Patients with Breast Cancer

“…7,8 Indeed, chronic inflammation and oxidative stress creates a proper microenvironment to promote tumor growth and metastasis in an obese person. 9 Breast tissue is largely made up of adipose tissue. Therefore, the role of the adipose tissue in initiation and progression of BC has been highlighted in various studies.…”