Leptin receptor expression and cell signaling in breast cancer

Abstract

Obesity is considered a risk factor for many cancers, including breast cancer. Our laboratory has previously shown that leptin is mitogenic in many cancer cell lines, including breast. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. In addition, SOCS-3 expression (a leptin inducible inhibitor of leptin signaling), plus MAPK and PI3K signaling, were examined to determine their role in leptin-induced cell proliferation. Breast cancer cell lines, ZR75-1 and HTB-26, were treated with 0, 4, 40 or 80 ng/ml of leptin. Multiplex RT-PCR was performed to determine relative mRNA expression levels of the human short (huOB-Ra) or long (huOB-Rb) leptin receptor isoforms, or SOCS-3. MAPK and PI3K signaling was analyzed by phosphorylation of ERK and Akt, respectively, via Western blotting. Cell proliferation and inhibitor studies were analyzed by MTT assay. HTB-26 and ZR75-1 both expressed huOB-Ra, huOB-Rb and SOCS-3 mRNA; however, mRNA expression levels generally remained unchanged over time with leptin treatment. MAPK and PI3K pathways were activated in the presence of leptin over time. MAPK and PI3K inhibitors significantly blocked leptin-induced proliferation. Higher levels of circulating leptin contribute to breast cancer proliferation by activation of the MAPK and PI3K signaling pathways involved in cell growth and survival. The mitogenic effects of leptin are not a consequence of altered leptin receptor or SOCS-3 mRNA expression.

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

“…MAPK and PI3K inhibitors markedly blocked leptin-induced proliferation (42). In human breast epithelial HBL100 cells and human breast carcinoma-derived T-47D cells, leptin increases the expression of phosphorylated STAT3 and P-ERK (31).…”

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…13 Diverse cancer cells derived from different tissues, such as brain, breast, colon or prostate, were reported to have ObR expression. [21][22][23][24][25] Furthermore, Ob-R overexpression not only correlated with the degree of malignancy, but also was an independent prognostic variable to predict poor progression-free survival in brain tumor, ovarian cancer, and breast cancer, 24,26,27 which suggested that ObR+ cells might be closely related with tumor initiation and development. In this study, we claimed that ObR+ glioblastoma cells presented chemoresistance, which showed that TMZ could not inhibit cell proliferation and could not induce apoptosis effectively.…”

Effects of adiponectin on breast cancer cell growth and signaling

“…However, the interplay between Acrp30 and other growth factors has been shown to be important for Acrp30's ability to inhibit cell proliferation (Wang et al, 2005). With respect to breast cancer, and obesity, leptin has been an adipokine implicated in mammary tumorigenesis (Hu et al, 2002;Cleary et al, 2003;Frankenberry et al, 2006;Garofalo et al, 2006). Overweight or obese individuals usually have elevated levels of the growth factor leptin, which is positively correlated to body mass index while Acrp30 is negatively correlated with body mass index.…”