The prevalence of obesity in the developed world has reached epidemic proportions in recent years. Recently, a study examining the relationship of obesity with mortality from breast cancer found that obese women in the highest quintile of body mass index (BMI) have double the death rate from breast cancer when compared with women in the lowest quintile. In addition, in women with BMI in the highest quintile, an increased proportion of tumors were ER negative, had a high S-phase fraction, histologic grade, mitotic cell count, expression levels of proliferation markers, and a larger tumor size. These clinical observations cannot be explained only by higher estrogen levels that are associated with obesity. Importantly, independent of their menopausal status, obese breast cancer patients exhibit a higher risk for lymph node metastasis, larger tumor burden and higher mortality when compared with non-obese breast cancer patients. Thus, understanding the molecular mechanism by which obesity adversely affects the prognosis of breast cancer patients is critical in order to help devise appropriate new approaches to their treatment. Obesity affects breast carcinogenesis by autocrine and paracrine actions mediated by two major adipocytokines, leptin and adiponectin. Our recent studies investigating the oncogenic actions of leptin revealed that - i) leptin induces proliferation via Stat3 activation, ii) leptin induces invasion and migration, and iii) leptin interferes with endocrine treatment. Displaying opposing effects, adiponectin reduces invasion and migration of breast cancer cells. Adiponectin activates AMPK in an LKB1-dependent manner, and inhibits S6K activation demonstrating the involvement of LKB1-AMPK-S6K axis. Most importantly, adiponectin treatment blocks some important steps of leptin signaling. These data strongly suggest that adiponectin antagonizes the cancer-promoting effects of leptin on breast cancer cells. Our research efforts are focused on investigating the molecular mechanism by which adiponectin impedes leptin signaling and biological effects.
Aimi ng to develop novel biomarkers to predict obesity related endocrine resistance, we will examine the important components of adiponectin and leptin signaling in clinically annotated human breast tumor samples using automated immunohistochemical analysis. Considering the high prevalence of obesity in the US, our study has the potential to significantly impact the vast majority of breast cancer patients with high leptin levels by improving their treatment response and overall survival.

Public Health Relevance

This project will investigate a novel concept that adipocytokine adiponectin antagonizes the pro-cancerous effects of adipocytokine leptin and hence have a protective role in breast carcinogenesis. We will elucidate the crosstalk between adiponectin and leptin signaling. In vivo studies proposed here will establish adiponectin as a novel negative regulator of breast cancer progression and metastasis providing the necessary pre-clinical data.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131294-06
Application #
8680019
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-07-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Xie, Bei; Nagalingam, Arumugam; Kuppusamy, Panjamurthy et al. (2017) Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes. Sci Rep 7:40070
Avtanski, Dimiter B; Nagalingam, Arumugam; Tomaszewski, Joseph E et al. (2016) Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis. Mol Oncol 10:1118-32
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Feitelson, Mark A; Arzumanyan, Alla; Kulathinal, Rob J et al. (2015) Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 35 Suppl:S25-S54
Avtanski, Dimiter B; Nagalingam, Arumugam; Bonner, Michael Y et al. (2015) Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget 6:29947-62
Avtanski, Dimiter B; Nagalingam, Arumugam; Kuppusamy, Panjamurthy et al. (2015) Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-?-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget 6:16396-410
Nagalingam, Arumugam; Kuppusamy, Panjamurthy; Singh, Shivendra V et al. (2014) Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer. Cancer Res 74:2617-29
Avtanski, Dimiter B; Nagalingam, Arumugam; Bonner, Michael Y et al. (2014) Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol 8:565-80
Saxena, Neeraj K; Sharma, Dipali (2013) Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia 18:309-20
Sharma, Dipali; Sukumar, Saraswati (2013) Big punches come in nanosizes for chemoprevention. Cancer Prev Res (Phila) 6:1007-10

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