Leptin as a Potential Target for Estrogen Receptor-Positive Breast Cancer

Purpose Leptin is a potent adipokine that plays a significant role in tumor development and the progression of breast cancer. The aim of this study was to evaluate whether leptin affects the response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancer cells. Methods Leptin, leptin receptor (Ob-R), and activation of signaling pathways were studied by Western immunoblotting. The effects of leptin on tamoxifen-dependent growth inhibition were studied in MCF-7 and T-47D cells. Results Leptin was expressed in MCF-7 and T-47D and had a proliferative effect on MCF-7 cells. Leptin significantly inhibited the antiestrogenic effect of tamoxifen in both cells only under β-estradiol (E2) (20 nM) conditions. In MCF-7, the inhibitory effect against tamoxifen was a result from the activation of the ERK1/2 and STAT3 signal transduction pathway. Conclusion Leptin interferes with the effects of tamoxifen under E2 stimulated conditions in ER-positive breast cancer cells. These results imply that inhibition of leptin is expected to enhance the response to tamoxifen in ER-positive breast cancer cells, and, therefore, could be a promising way to overcome endocrine resistance.

[1]  Yongmei Yin,et al.  Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer. , 2013, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[2]  G. Spalletta,et al.  Overcoming endocrine resistance in breast cancer. , 2010, Current cancer drug targets.

[3]  S. Wessler,et al.  Expression of estrogen receptor alpha increases leptin‐induced STAT3 activity in breast cancer cells , 2010, International journal of cancer.

[4]  G. Colditz,et al.  Obesity and Cancer , 2010, The oncologist.

[5]  Berta M. Geller,et al.  Risk factors for breast carcinoma in situ versus invasive breast cancer in a prospective study of pre- and post-menopausal women , 2007, Breast Cancer Research and Treatment.

[6]  D. Rose,et al.  Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. , 2007, Endocrine-related cancer.

[7]  Didier Merlin,et al.  Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. , 2007, Cancer research.

[8]  E. Surmacz.  Obesity hormone leptin: a new target in breast cancer? , 2007, Breast Cancer Research.

[9]  M. Hou,et al.  Serum adiponectin and leptin levels in Taiwanese breast cancer patients. , 2006, Cancer letters.

[10]  A. Russo,et al.  Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli , 2006, Clinical Cancer Research.

[11]  E. Surmacz,et al.  Leptin Interferes with the Effects of the Antiestrogen ICI 182,780 in MCF-7 Breast Cancer Cells , 2004, Clinical Cancer Research.

[12]  C. Giordano,et al.  Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor α in MCF-7 Cells* , 2004, Journal of Biological Chemistry.

[13]  A. Bado,et al.  Leptin Counteracts Sodium Butyrate-induced Apoptosis in Human Colon Cancer HT-29 Cells via NF-κB Signaling* , 2004, Journal of Biological Chemistry.

[14]  J. Bub,et al.  Prostate Cancer Cell-Adipocyte Interaction , 2003, Journal of Biological Chemistry.

[15]  Angélique Gougelet,et al.  Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor α (ERα), Differentially Affect ERα Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells , 2003 .

[16]  S. Cummings,et al.  Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. , 2003, Journal of the National Cancer Institute.

[17]  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.

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

[19]  D. Rose,et al.  Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). , 2002, International journal of oncology.

[20]  M. Dieudonné,et al.  Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue , 2002, Endocrine.

[21]  G. Chrousos,et al.  Leptin inhibits steroid biosynthesis by human granulosa-lutein cells. , 2001, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[22]  I. Robinson,et al.  Leptin receptor 5′untranslated regions in the rat: relative abundance, genomic organization and relation to putative response elements , 2001, Molecular and Cellular Endocrinology.

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

[24]  J. Kitawaki,et al.  Leptin directly stimulates aromatase activity in human luteinized granulosa cells. , 1999, Molecular human reproduction.

[25]  R. Busse,et al.  Leptin, the product of Ob gene, promotes angiogenesis. , 1998, Circulation research.

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

[27]  I. Robinson,et al.  Differential Expression and Regulation of Leptin Receptor Isoforms in the Rat Brain: Effects of Fasting and Oestrogen , 1998, Neuroendocrinology.

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

[29]  L. Spicer,et al.  The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function. , 1997, Endocrinology.

[30]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[31]  C. Giordano,et al.  Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. , 2004, The Journal of biological chemistry.

[32]  Angélique Gougelet,et al.  Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor alpha (ERalpha), differentially affect ERalpha extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. , 2003, Molecular endocrinology.