Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli

Abstract

Purpose: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesityrelated stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. Experimental Design: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. Results: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231cells. Conclusions: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol.

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.…”

Functional analysis of the ‐2548G/A leptin gene polymorphism in breast cancer cells

“…9 Tissue samples were obtained from women who underwent partial or total mastectomy for primary breast cancer. The age of patients ranged from 45 to 71 years.…”

“…[6][7][8] Interestingly, overexpression of the leptin system in breast cancer appears to be associated with higher tumor grade and size. [9][10][11][12][13] The mechanisms of leptin overexpression in breast cancer cells is partially known, for instance, we have shown that leptin transcription and synthesis can be induced by hypoxia or high levels of insulin. 9,13,14 Here we investigated whether leptin expression in breast cancer cells could be related to the existence of the Lep-2548G/A polymorphism in the promoter region of leptin gene.…”

IL‐1 family in breast cancer: Potential interplay with leptin and other adipocytokines

“…Both leptin and ObR expressions are more abundant in tumours with a high grade [57]. Interestingly, leptin and ObR are co-expressed in primary breast carcinoma, suggesting that leptin acts on mammary tumour cells via an autocrine pathway [55].…”