Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.

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Tumor uptake of exogenous cholesterol has been associated with the proliferation of various cancers. Previously, we and others have shown that hypercholesterolemia promotes tumor growth and silencing of the LDL receptor (LDLR) in high LDLR-expressing tumors reduces growth. To advance understanding on how LDL uptake promotes tumor growth, LDLR expression was amplified in breast cancer cell lines with endogenously low LDLR expression. Murine (Mvt1) and human (MDA-MB-468) breast cancer cell lines were transduced to overexpress human LDLR (LDLROE). Successful transduction was confirmed by RNA and protein analysis. Fluorescence-labelled LDL uptake was increased in both Mvt1 and MDA-MD-468 LDLROE cells. Expression of the cholesterol metabolism genes, ABCA1 and ABCG1, was increased while HMGCR was decreased in the MDA-MB-468 LDLROE cells. In contrast, Mvt1 LDLROE cells showed no differences in Abca1 and Abcg1 expression and increased Hmgcr expression. Using a Seahorse analyzer, Mvt1 LDLROE cells showed increased respiration (ATP-linked and maximal) relative to controls while no statistically significant changes in respiration in MDA-MB-468 LDLROE cells were observed. Growth of LDLROE cells was reduced in culture and in hypercholesterolemic mice by 2-fold. However, the expression of proliferation-associated markers (Ki67, PCNA and BrdU-label incorporation) was not decreased in the Mvt1 LDLROE tumors and cells. Caspase-3 cleavage, which is associated with apoptosis, was increased in both the Mvt1 and MDA-MB-468 LDLROE cells relative to controls, with the Mvt1 LDLROE cells also showing decreased phosphorylation of p44/42MAPK. Taken together, our work suggests that while additional LDL can promote tumor growth, unregulated and prolonged LDL uptake is detrimental.

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Systemic hyperinsulinemia is believed to be an important factor in the progression of a number of cancers, including breast cancer by activating the insulin receptor (IR) signaling cascade in the tumor cells. The IR is expressed in two isoforms, IR-A and IR-B. IR-B is the full-length isoform, while IR-A is lacking 12 amino acids in the α-subunit due to exon 11 alternative splicing. IR-A is predominantly expressed in cancer tissues, while IR-B is mostly expressed in metabolic tissues. The IR and closely related insulin-like growth factor 1 receptor (IGF-1R) are expressed in different ratios in cancer cells. Compared with estrogen receptor positive breast cancers, triple negative breast cancers (TNBC) frequently have higher ratios of IR to IGF-1R. Hyperinsulinemia is associated with increased prevalence of TNBC in pre-menopausal women. Although new targeted therapies are emerging, among breast cancer subtypes TNBC continues to carry the worst prognosis and therefore developing a greater understanding of the links between IR signaling and TNBC progression is critical. The aim of this study is to understand the role of IR-A and IR-B on proliferation, metastasis and metabolism in breast cancer cells. We stably overexpressed human IR-A (IR-A OE) and IR-B (IR-B OE) in TNBC MDA-MB-231 (231) and murine c-myc/vegf overexpressing Mvt1 cells with lentiviral transduction using pLVX-IRES-puro HIV-1-based expression vectors with cDNA encoding the human IR-A,IR-B and control cDNA sequences. Native murine IR was silenced using lentiviral transduction of shRNA in the Mvt1 cells. Overexpression of IR was confirmed at a protein level by western blot, and RNA isoform expression was confirmed using real time PCR. Cell proliferation assays were performed in DMEM/10% FBS and revealed that MDA-MB-231 cells with IR-A OE cells had 15% higher proliferation rates than 231 IR-B OE cells. We then examined the IR signaling pathways by western blot in DMEM/10% FBS. No differences in phosphorylated or total ERK1/2 were observed between control, 231 IR-A OE and 231 IR-B OE cells. 231 IR-A OE cells were found to have 15-fold greater Akt phosphorylation (Ser473) than 231 control cells (p=0.0008) and 4 fold higher pAkt(Ser473) compared with 231 IR-B OE cells (p=0.0016). Further, we found that 231 IR-A OE cells had approximately 2 fold greater expression of c-myc protein compared with both 231 control (p=0.047) and 231 IR-B OE cells (p=0.026). No differences in c-myc expression were observed between 231 IRB OE and 231 control cells. In our previous studies we found that insulin stimulates c-myc expression and silencing the IR reduces c-myc expression in cancer cells. Our current studies show that IR-A, rather than IR-B is the insulin receptor isoform that regulates c-myc expression in human TNBC. Reference: (1) Belfiore et al., Endocr Relat Cancer. 2011; 18(4):R125-R147. (2) Ferguson et al., Breast Cancer Res. 2012; 14(1): R8.