Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli
Open accessAbstract
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 obesity-related 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-231 cells, 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-231 cells. 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This could lead to promotion of a pro-resting cancer stem cell niche for the most therapy-resistant stem-like cells, or to recruitment and promotion of tumorigenesis for more active progenitor cells.
“This may result into promotion of a pro-resting CSC niche [152, 153] for the most therapy-resistant stem-like cells, or recruitment and promotion of tumorigenesis for more active progenitor cells.”
From Mesenchymal stem cell secretome and regenerative therapy after cancer (2013) · cites this paper as [153]
The Discussion reports that leptin and its receptor negatively correlated with Ki-67 in metastases, but it does not connect that observation to a resting cancer stem-cell niche. Searches for quiescent, therapy-resistant stem-like cells and progenitor-cell recruitment found no passage addressing the cited claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Pathology and Genetics of Tumours of the Breast and Female Genital Organs
Tavassoli, F. A., & Devilee, P. (2003) · International Agency for Research on Cancer eBooks · Cited by 2,818 · see citing works
Calle, E. E., & Thun, M. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207751 · Cited by 791 · see citing works
Hormonal Regulation of Mammary Differentiation and Milk Secretion
Neville, M. C., McFadden, T. B., & Forsyth, I. A. (2002) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/a:1015770423167 · Cited by 628 · see citing works
Garofalo, C., & Surmacz, E. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20472 · Cited by 591 · see citing works
Self-citationHuman leptin: from an adipocyte hormone to an endocrine mediator
Wauters, M., Considine, R. V., & Gaal, L. V. (2000) · European Journal of Endocrinology · doi:10.1530/eje.0.1430293 · Cited by 458 · see citing works
Hu, X. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.22.1704 · Cited by 451 · see citing works
Enhanced Expression of Leptin and Leptin Receptor (OB-R) in Human Breast Cancer
Ishikawa, M., Kitayama, J., & Nagawa, H. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0749 · Cited by 443 · see citing works
Leptin Expression in Human Mammary Epithelial Cells and Breast Milk
Kirwin, S. M., O’Connor, D. M., Johnston, J. J., et al. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.5.4952 · Cited by 415 · see citing works
Leptin mediates a proliferative response in human MCF7 breast cancer cells
Dieudonné, M., Machinal-Quélin, F., Serazin-Leroy, V., Leneveu, M.-C., Pecquery, R., & Giudicelli, Y. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00205-x · Cited by 286 · see citing works
Leptin Enhances, via AP-1, Expression of Aromatase in the MCF-7 Cell Line
Catalano, S., Marsico, S., Giordano, C., Mauro, L., Rizza, P., Panno, M. L., & Andò, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301695200 · Cited by 285 · see citing works
Expression of ob Gene in Adipose Cells
Leroy, P., Dessolin, S., Villageois, P., Moon, B. C., Friedman, J. M., Ailhaud, G. P., & Dani, C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.5.2365 · Cited by 280 · see citing works
The ob Gene and Insulin: A Relationship Leading to Clues to the Understanding of Obesity
Cusin, I., Sainsbury, A., Doyle, P., Rohner‐Jeanrenaud, F., & Jeanrenaud, B. (1995) · Diabetes · doi:10.2337/diab.44.12.1467 · Cited by 276 · see citing works
Sweeney, G. (2002) · Cellular Signalling · doi:10.1016/s0898-6568(02)00006-2 · Cited by 271 · see citing works
Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor α in MCF-7 Cells
Catalano, S., Mauro, L., Marsico, S., Giordano, C., Rizza, P., Rago, V., Montanaro, D., Maggiolini, M., Panno, M. L., & Andò, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313191200 · Cited by 266 · see citing works
Hypoxia-inducible Factor 1 Transactivates the Human Leptin Gene Promoter
Grosfeld, A., André, J., Mouzon, S. H., Berra, E., Pouysségur, J., & Guerre-Millo, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206775200 · Cited by 263 · see citing works
Breast Cancer and Obesity: An Update
Stephenson, G. D., & Rose, D. P. (2003) · Nutrition and Cancer · doi:10.1207/s15327914nc4501_1 · Cited by 258 · see citing works
Function of the IGF-I Receptor in Breast Cancer
Surmacz, E. (2000) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/a:1009523501499 · Cited by 215 · see citing works
Self-citationOkumura, M., Yamamoto, M., Sakuma, H., et al. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(02)00276-8 · Cited by 210 · see citing works
Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.
Helczynska, K., Kronblad, Å., Jögi, A., Nilsson, E., Beckman, S., Landberg, G., & Påhlman, S. (2003) · PubMed · Cited by 202 · see citing works
Differential effects of leptin on cancer in vitro
Somasundar, P. S., Yu, A., Vona-Davis, L. C., & McFadden, D. W. (2003) · Journal of Surgical Research · doi:10.1016/s0022-4804(03)00166-5 · Cited by 202 · see citing works
Laud, K., Gourdou, I., Pessemesse, L., et al. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00678-5 · Cited by 191 · see citing works
Transcriptional Activation of the Human Leptin Gene in Response to Hypoxia
Ambrosini, G., Nath, A. K., Sierra-Honigmann, M. R., & Flores-Riveros, J. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205172200 · Cited by 188 · see citing works
Molecular Mechanisms Involved in the Growth Stimulation of Breast Cancer Cells by Leptin
Yin, N., Wang, D., Zhang, H., Yi, X., Sun, X., Shi, B., Wu, H., Wu, G., Wang, X., & Shang, Y. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0655 · Cited by 180 · see citing works
Bartucci, M., Morelli, C., Mauro, L., Andò, S., & Surmacz, E. (2001) · PubMed · Cited by 172 · see citing works
Self-citationCarbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma
Watson, P. H., Chia, S., Wykoff, C. C., Han, C., Leek, R., Sly, W. S., Gatter, K. C., Ratcliffe, P. J., & Harris, A. L. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6600796 · Cited by 147 · see citing works
Genetically Obese MMTV-TGF-α/Lep ob Lep ob Female Mice do not Develop Mammary Tumors
Cleary, M. P., Phillips, F. C., Getzin, S. C., Jacobson, T. L., Jacobson, M. K., Christensen, T. A., Juneja, S. C., Grande, J. P., & Maihle, N. J. (2003) · Breast Cancer Research and Treatment · doi:10.1023/a:1021891825399 · Cited by 146 · see citing works
Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (Review)
Rose, D. P., Gilhooly, E. M., & Nixon, D. W. (2002) · International Journal of Oncology · doi:10.3892/ijo.21.6.1285 · Cited by 144 · see citing works
Leptin Interferes with the Effects of the Antiestrogen ICI 182,780 in MCF-7 Breast Cancer Cells
Garofalo, C., Sisci, D., & Surmacz, E. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0203 · Cited by 139 · see citing works
Self-citationOestrogen receptor β: what it means for patients with breast cancer
Speirs, V., Carder, P. J., Lane, S., Dodwell, D. J., Lansdown, M., & Hanby, A. M. (2004) · The Lancet Oncology · doi:10.1016/s1470-2045(04)01413-5 · Cited by 134 · see citing works
Presence of Leptin in Breast Cell Lines and Breast Tumors
O’Brien, S. N., Welter, B. H., & Price, T. M. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0843 · Cited by 120 · see citing works
Insulin receptors in breast cancer: Biological and clinical role
Papa, V., & Belfiore, A. (1996) · Journal of Endocrinological Investigation · doi:10.1007/bf03347871 · Cited by 116 · see citing works
Machinal-Quélin, F., Dieudonné, M., Pecquery, R., Leneveu, M.-C., & Giudicelli, Y. (2002) · Endocrine · doi:10.1385/endo:18:2:179 · Cited by 103 · see citing works
The ob gene and insulin. A relationship leading to clues to the understanding of obesity
Cusin, I., Sainsbury, A., Doyle, P. H., et al. (1995) · Diabetes · doi:10.2337/diabetes.44.12.1467 · Cited by 83 · see citing works
Mauro, L., Salerno, M., Morelli, C., Boterberg, T., Bracke, M., & Surmacz, E. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10207 · Cited by 81 · see citing works
Self-citationNuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters
Morelli, C., Garofalo, C., Sisci, D., et al. (2004) · Oncogene · doi:10.1038/sj.onc.1208014 · Cited by 79 · see citing works
Self-citationSurmacz, E., & Bartucci, M. (2004) · PubMed · Cited by 72 · see citing works
Self-citationMorelli, C., Garofalo, C., Bartucci, M., & Surmacz, E. (2003) · Oncogene · doi:10.1038/sj.onc.1206436 · Cited by 62 · see citing works
Self-citationO’Neil, J. S., Burow, M. E., Green, A. E., et al. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00473-7 · Cited by 57 · see citing works
Sauter, E. R., Garofalo, C., Hewett, J. E., Hewett, J. E., Morelli, C., & Surmacz, E. (2004) · Hormone and Metabolic Research · doi:10.1055/s-2004-814490 · Cited by 46 · see citing works
Self-citationHypoxia Inducible Factor Pathways as Targets for Functional Foods
Losso, J. N., & Bawadi, H. A. (2005) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf0479719 · Cited by 34 · see citing works
Guastamacchia, E., Resta, F., Triggiani, V., Liso, A., Licchelli, B., Ghiyasaldin, S., Sabbà, C., & Tafaro, E. (2004) · Current Drug Targets - Immune Endocrine & Metabolic Disorders · doi:10.2174/1568008043339965 · Cited by 26 · see citing works
Choi, Y. J., & Pinto, M. M. (2005) · Applied immunohistochemistry & molecular morphology · doi:10.1097/00129039-200503000-00004 · Cited by 26 · see citing works
Expression of ERα, ERβ and Ki-67 in primary tumors and lymph node metastases in breast cancer
Koda, M., Sulkowski, S., Koda, M., Surmacz, E., & SULKOWSKA, M. (2004) · Oncology Reports · doi:10.3892/or.11.4.753 · Cited by 21 · see citing works
Self-citation[Influence of hypoxia on leptin and leptin receptor gene expression of C57BL/6J mice].
Liu, X., Wu, Y.-M., Xu, L., et al. (2005) · PubMed · Cited by 4 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Grosfeld A, Andre J, Hauguel-De Mouzon S, Berra E, Pouyssegur J, Guerre-Millo M. Hypoxia-inducible factor1transactivates the human leptin gene promoter. J Biol Chem 2002;277:42953 ^7.
Cited by
Sorted by citations
Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression
Vona-Davis, L., & Rose, D. P. (2007) · Endocrine-Related Cancer · doi:10.1677/erc-06-0068 · Cited by 496 · see citing works
Wang, B., Wood, I. S., & Trayhurn, P. (2007) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-007-0301-8 · Cited by 392 · see citing works
Mesenchymal stem cell secretome and regenerative therapy after cancer
Zimmerlin, L., Park, T. S., Zambidis, E. T., Donnenberg, V. S., & Donnenberg, A. D. (2013) · Biochimie · doi:10.1016/j.biochi.2013.05.010 · Cited by 168 · see citing works
“The effects of a few secreted factors unique to adipose derived MSC, such as leptin and adipsin, remain unclear, although, leptin has been associated with tumor progression in breast cancer [154].”
BackgroundChallenges and Perspectives in the Treatment of Diabetes Associated Breast Cancer
Samuel, S. M., Varghese, E., Varghese, S., & Büsselberg, D. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.08.004 · Cited by 141 · see citing works
Gérard, C., & Brown, K. A. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.09.014 · Cited by 136 · see citing works
Cascio, S., Ferla, R., D'Andrea, A., Gerbino, A., Bazan, V., Surmacz, E., & Russo, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21843 · Cited by 53 · see citing works
Self-citation
- Authors
- Garofalo, C., Koda, M., Cascio, S., Sulkowska, M., Kanczuga-Koda, L., Golaszewska, J., Russo, A., Sulkowski, S., & Surmacz, E.
- Affiliations
- University of Calabria (IT)
- 3Department of Pathology, Medical University of Bialystok, Bialystok, Poland; and
- Temple University (US)
- Medical University of Białystok (PL)
- University of Palermo (IT)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2006-03-01
- Volume
- 12
- Issue
- 5
- Pages
- 1447-1453
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2170924429
- Cited by
- 370
- References
- 44
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 8 · 2023: 16 · 2022: 21 · 2021: 27 · 2020: 20 · 2019: 21 · 2018: 12 · 2017: 16 · 2016: 16 · 2015: 19 · 2014: 20 · 2013: 34 · 2012: 28
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, leptin receptor, breast cancer, breast cancer metastasis, obesity, insulin, insulin-like growth factor I, estradiol, hypoxia, autocrine signaling, tumor progression markers, MCF-7 cells, MDA-MB-231 cells
- MeSH terms
- Adult, Aged, Aged, 80 and over, Breast, Breast Neoplasms, Estradiol, Female, Humans, Insulin, Insulin-Like Growth Factor I, Middle Aged, Neoplasms, Obesity, Receptors, Cell Surface, Tumor Cells, Cultured, Biomarkers, Tumor, Cell Hypoxia, Case-Control Studies, Carcinoma, Ductal, Breast, Disease Progression, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Receptors, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
