Effects of Obesity on Transcriptomic Changes and Cancer Hallmarks in Estrogen Receptor–Positive Breast Cancer

Abstract

BackgroundObesity increases the risk of cancer death among postmenopausal women with estrogen receptor–positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon.MethodsWe analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A y /a) and orthotopic/syngeneic (A y /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided.ResultsFunctional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial–mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6–7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6–8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro.ConclusionsAdipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity.

Obesity and Cancer: Jet Fuel Accelerating Cancer Hallmarks and Increasing the Economic Burden of Cancer

“…MCP-1, RAGE and resist in also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich adipose-derived peptide hormone that in humans is encoded by the RETN gene have been related to metastasis, [12][13][14][15] while TIMP1 has been related to chemotherapy resistance, cancer cell proliferation and cancer aggressiveness. [16][17][18] There is no evidence showing that obesity is involved in the carcinogenesis process inducing the transformation of normal cells into malignant cancer cells. In contrast, it is clear that obesity is accelerating carcinogenesis and tumor growth enhancing cancer hallmarks.…”

“…In contrast, it is clear that obesity is accelerating carcinogenesis and tumor growth enhancing cancer hallmarks. 16 In other words, obesity is more like jet fuel in predisposed cancer patients. Obesity is known to increase (orange box) adipokines (e.g., Fetuin A, IL-6, Leptin, MCP-1, TIMP-1, VEGF) and signaling pathways (e.g., PI3K/AKT/mTOR, WNT) that can promote cancer, and to decrease (green box) other adipokines (e.g., Adiponectin, Lipocalin-2) that are negatively correlated with cancer.…”

“…In contrast, disruptions of the obesity-induced energy balance via exercise, caloric restriction, [19][20][21] or pharmacologically (e.g., metformin) can reduce tumor cell proliferation and growth. 16,22,23 Indeed, obesity is associated with mild or severe (as part of diabetes type 2 comorbidity) systemic hyperglycemia and insulin resistance with hyperinsulinemia. However, studies with adipocytes co-culture model showed that mature adipocytes humorally accelerate cancer cell proliferation.…”

“…However, studies with adipocytes co-culture model showed that mature adipocytes humorally accelerate cancer cell proliferation. 16 Metformin is a biguanide, well established and effective anti-insulin resistance agent that can lowers systemic circulating glucose levels and increase insulin sensitivity. At the molecular level, metformin inhibits the PI3K/AKT/mTOR pathway, fatty acid biosynthesis and chronic inflammation via the inhibition of mitochondrial complex I and the LKB1/AMPK signaling pathway.…”

“…24,25 More recently, we showed that metformin treatment disrupted lipid accumulation and adipocyte maturation during adipocytes differentiation, while metformin treatment can decrease adipokine secretion in vitro and in vivo. 16 Thus, we can speculate that the obesity microenvironment is providing the essential energy building blocks (e.g., glucose, amino acids, fatty acids) for DNA synthesis and cell membrane expansion must needed for cell proliferation. However, there are many aspects of obesity-promoted cancer metabolisms that are still not well understood in order to develop more efficient targeted-therapy strategies.…”