High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels

The association of mRNA expression levels of leptin receptors (long isoform: Lep‐R(L) and short isoform: Lep‐R(S)) in breast cancer tissue with patient prognosis was studied with special reference to the serum leptin level or the leptin mRNA level in tumor tissue. Lep‐R(L), Lep‐R(S) and leptin mRNA levels in breast cancer tissue (n = 91) were determined with a real‐time PCR assay, and serum leptin levels in breast cancer patients (n = 67) with an enzyme‐linked immunosorbent assay. Neither Lep‐R(L) nor Lep‐R(S) mRNA levels in tumor tissue were significantly associated with patient prognosis, but both intratumoral Lep‐R(L) and Lep‐R(S) mRNA high tumors were significantly (p < 0.01) associated with a poor prognosis. Multivariate analysis showed that a high level of both Lep‐R (L) and Lep‐R (S) mRNA in tumor tissue was a significant risk factor, independent of other risk factors. The subset analysis demonstrated that both intratumoral Lep‐R(L) and Lep‐R(S) mRNA high tumors were significantly associated with a poor prognosis for the subset of patients with high serum leptin or high intratumoral leptin mRNA levels but not in the subset of patients with low serum leptin or low intratumoral leptin mRNA levels. The association between both intratumoral Lep‐R(L) and Lep‐R(S) mRNA high tumors and a poor prognosis in the presence of high serum leptin or high intratumoral leptin mRNA levels seems to suggest that the leptin and Lep‐R(L)/Lep‐R(S) pathways are implicated in the growth stimulation of breast tumors. The well‐established finding that obesity serves as a risk factor for relapse in breast cancer patients may thus be partially explained by the high serum leptin level seen in obese women. © 2005 Wiley‐Liss, Inc.

[1]  R. Gelber,et al.  Fifth International Conference on Adjuvant Therapy of Breast Cancer, St Gallen, March 1995. International Consensus Panel on the Treatment of Primary Breast Cancer. , 1995, European journal of cancer.

[2]  L. Tessitore,et al.  Leptin expression in colorectal and breast cancer patients. , 2000, International journal of molecular medicine.

[3]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[4]  L. Tartaglia,et al.  Leptin and OB-R: body weight regulation by a cytokine receptor. , 1996, Cytokine & growth factor reviews.

[5]  A. McTiernan,et al.  Weight loss in breast cancer patient management. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Y. Nomura,et al.  Survival of breast‐cancer patients and body size indicators , 1990, International journal of cancer.

[7]  P. Bischof,et al.  Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. , 2000, Molecular human reproduction.

[8]  C. Tsigos,et al.  Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin's actions. , 2000, Metabolism: clinical and experimental.

[9]  A. Ozet,et al.  Effects of tamoxifen on the serum leptin level in patients with breast cancer. , 2001, Japanese journal of clinical oncology.

[10]  R. Considine,et al.  Serum immunoreactive-leptin concentrations in normal-weight and obese humans. , 1996, The New England journal of medicine.

[11]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[12]  T. Murakami,et al.  Leptin receptor signal transduction: OBRa and OBRb of fa type. , 1998, Biochemical and biophysical research communications.

[13]  Xin Hu,et al.  Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development. , 2003, Journal of the National Cancer Institute.

[14]  R. Gelber,et al.  International Consensus Panel on the treatment of primary breast cancer. V: Update 1998. , 1995, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[15]  Ju Yong Lee,et al.  Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro , 2001, Experimental & Molecular Medicine.

[16]  J. Peyrat,et al.  Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line , 2002, Molecular and Cellular Endocrinology.

[17]  M. Dieudonné,et al.  Leptin mediates a proliferative response in human MCF7 breast cancer cells. , 2002, Biochemical and biophysical research communications.

[18]  R. Lang,et al.  Radiommunological measurement of leptin in plasma of obese and diabetic human subjects. , 1996, Endocrinology.

[19]  R. Darnell,et al.  Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Grande,et al.  Genetically Obese MMTV-TGF-α/LepobLepob Female Mice do not Develop Mammary Tumors , 2003, Breast Cancer Research and Treatment.

[21]  J. Friedman,et al.  Abnormal splicing of the leptin receptor in diabetic mice , 1996, Nature.

[22]  J. Flier,et al.  Divergent Signaling Capacities of the Long and Short Isoforms of the Leptin Receptor* , 1997, The Journal of Biological Chemistry.

[23]  J. McLachlan,et al.  Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta. , 2001, Molecular and cellular endocrinology.

[24]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[25]  H. Nagawa,et al.  Enhanced Expression of Leptin and Leptin Receptor (OB-R) in Human Breast Cancer , 2004, Clinical Cancer Research.

[26]  J. Grande,et al.  Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors. , 2003, Breast cancer research and treatment.

[27]  J. Ohannesian,et al.  Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. , 1996, The Journal of clinical investigation.

[28]  P. Stattin,et al.  Plasma Leptin and Breast Cancer Risk: A Prospective Study in Northern Sweden , 2004, Breast Cancer Research and Treatment.

[29]  Founding Editor,et al.  Adjuvant Therapy of Primary Breast Cancer , 1989, Recent Results in Cancer Research.

[30]  K. Satomura,et al.  Potential Role of Leptin in Endochondral Ossification , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[31]  C. Giordano,et al.  Leptin Enhances, via AP-1, Expression of Aromatase in the MCF-7 Cell Line* , 2003, Journal of Biological Chemistry.

[32]  C. Mantzoros,et al.  Leptin in relation to carcinoma In situ of the breast: A study of pre‐menopausal cases and controls , 1999, International journal of cancer.

[33]  D. Trichopoulos,et al.  Leptin and insulin growth factor I in relation to breast cancer (Greece) , 2000, Cancer Causes & Control.

[34]  J. McLachlan,et al.  Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors α and β , 2001, Molecular and Cellular Endocrinology.

[35]  D. Rose,et al.  Obesity, adipocytokines, and insulin resistance in breast cancer , 2004, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[36]  L. Tartaglia,et al.  The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S Friedman,et al.  Prognostic value of histologic grade nuclear components of Scarff‐Bloom‐Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas , 1989, Cancer.