Abstract
IntroductionObesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.MethodsBreast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.ResultsASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.ConclusionASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.
Highlights
Obesity has been associated with increased incidence and mortality of breast cancer
adipose stem cells (ASCs) isolated from obese subjects enhance the proliferation of MCF7 cells in vitro To investigate the effect of the donor’s body mass index (BMI) status and depot site on ASC interaction with breast cancer cells, MCF7 cells or MDA-MB-231 cells were directly cocultured with ASCs from non-abdominal sources of nonobese subjects (Ob-Ab-), abdominal source of non-obese subjects (Ob-Ab+), non-abdominal sources of obese subjects (Ob+Ab-), or abdominal sources of obese subjects (Ob+Ab+)
The results demonstrated that the mRNA expression levels of eight genes were altered between the Ob-Ab+ ASCs, Ob+Ab- ASCs and Ob+Ab+ ASCs when compared to Ob-Ab- ASCs: leptin (LEP), leptin receptor (LEPR), sortilin 1 (SORT1), thyrotropin-releasing hormone (TRH), melanin-concentrating hormone 1 (MCHR1), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), peroxisome proliferator-activated receptor gamma coactivator 1-α (PPARGC1A) and thyroid hormone receptor-β (THRB) (P
Summary
Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression. ASCs are mesenchymal lineage stem cells that are recruited to the tumor or sites of inflammation and are essential components that establish the tumor microenvironment [11,12,13] This recruitment enhances tumor growth through the secretion of an abundance of growth factors from ASCs, such as IL-6, CCL5 and PDGR, which have been shown to contribute to both the breast cancer tumorigenesis and the metastasis of breast cancer cells [14,15]. Recent work by Kolonin et al demonstrated increased numbers of ASC in obese mice relative to lean mice, and this increase in ASC number enhances vascularization and proliferation of malignant cells [13] The results from these studies suggest that the local microenvironment from which these ASCs are isolated can influence their gene expression profiles. The site of origin of the adipose tissue from which the ASCs are derived may alter essential cellular signaling pathways that may directly influence breast cancer tumorigenesis
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