The Potential Role of Insulin (and Stress Response) Pathway Components In Breast Cancer Development and Progression

Breast cancer is characterized into several subtypes, which are further classified by the status of three central receptors: estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu). These subtypes differ according to etiology, tumor grade, clinical outcomes, and responses to therapeutic agents. In fact, breast cancer tumor cells that lack tumor receptors (ER-, PR-, and/or Her2-) are indicative of breast cancer subtypes that are usually associated with poor prognosis and increased cancer progression. We hypothesize that SNPs in insulin-signaling pathway genes, IGF1, TSC1, IGFBP2, IRS1, TCF7L2, IGF1R, and PPARA, if significantly associated with tumor receptor status, provide evidence for a connection between insulin metabolism and the determination of breast tumor subtypes. The CC genotype of the TSC1 polymorphism rs7874234 was significantly associated with ER- breast cancer in patients below age 50 (p=0.015); whereas the CC genotype of the TCF7L2 polymorphism rs10885409 was significantly associated with Her2- among European-American patients (p=0.003) but not among African-American patients (p=1.00). We also observed significant differences between the allele frequencies of IRS1 rs13306465 of both European- and African-American breast cancer patients and samples of the corresponding local populations (p\u3c0.001 in both cases). These results demonstrate that, SNPs in the insulin-signaling pathway are associated with tumor receptor status in breast cancer patients. We have also investigated the phosphorylation of IRS1 Ser312 in breast cancer cells. Our results establish that IRS1 is not phosphorylated at Ser312 in breast cancer cells. However, an increase in PKR protein levels and endogenous kinase activity in breast cancer cells led us to examine PACT protein levels. PACT protein levels are also increased in several breast cancer cell lines. In contrast, PACT mRNA levels are increased in the non-transformed cell line. Using a PACT promoter constructs and via RT-PCR analysis, we conclude that regulation of PACT expression may occur at post-transcriptional levels