The condition of being overweight or obese has been implicated as a risk factor for breast cancer. According to the National Center for Health Statistics (NCHS), ~42.3% of women ages 50 and older in US are obese whose breast cancer risk is increased two- to four- fold. Furthermore, the current pandemic of obesity can potentially lead to a corresponding increase in breast cancer world-wide. There is a clear and compelling need to develop chemopreventive strategies to combat breast cancer in obese population. With an overall goal to develop effective chemopreventive strategies to target breast cancer in obese state, in this proposal, we will examine the molecular mechanism(s) whereby Benzyl isothiocyanate (BITC), a bioactive compound derived from cruciferous vegetables, prevents breast cancer growth in obese hyperleptinemic conditions. Research from our lab and others has shown that high leptin levels (hyperleptinemia) associated with obese state is a major driver of breast cancer progression and metastasis. Examining bioactive approaches to block leptin signaling, we recently discovered that BITC can effectively reduce leptin-induced proliferation and blocks leptin-induced migration potential of breast cancer cells. The project consists of two highly innovative aims.
Aim 1 will test whether BITC blocks leptin-induced epithelial-mesenchymal transition, inhibits leptin-signaling network and examine the role of miR-34a in mediating BITC actions. Our studies will establish BITC as an effective leptin- antagonist and dissect the underlying molecular interactions between BITC and leptin signaling axes potentially revealing new crosstalk.
Aim 2 will focus on examining whether BITC impedes paracrine actions of leptin and prevents breast carcinogenesis in hyperleptinemic obese state. Our preliminary findings show that the paracrine effect of leptin is important for adipocytes-breast cancer cells crosstalk leading to induction of EMT, invasion and migration potential of breast cancer cells. Results from this aim will decipher if BITC can block paracrine effects of leptin and prevent adipocytes-breast cancer cells crosstalk outcome. Our studies will advance the BITC chemoprevention field in a new direction showing the effectiveness of BITC in preventing breast cancer progression in obese conditions and establishing BITC as a novel leptin-antagonist. These studies will provide pre-clinical information to design clinical trials of BITC-based chemopreventive strategies for obese persons at high risk for developing breast cancer. It is important to note that obesity is attributed to ~90,000 cancer-related deaths/year in the USA therefore our findings will have far-reaching impact.
The overall goal of our studies is to examine the molecular mechanisms whereby BITC (Benzyl Isothiocyanate), an important bioactive compound from cruciferous vegetables, prevents breast cancer growth and progression in hyperleptinemic obese conditions. We will investigate targets mediating chemopreventive function of BITC as well as examine its leptin-antagonistic actions. These innovative studies will provide a scientific basis for the in vivo efficacy of BITC in antagonizing leptin's pro-neoplastic actions and, we anticipate, will lead to BITC-based chemopreventive regimens for obese breast cancer patients.
|Chung, Seung J; Nagaraju, Ganji Purnachandra; Nagalingam, Arumugam et al. (2017) ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis. Autophagy 13:1386-1403|
|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|
|Sengupta, S; Nagalingam, A; Muniraj, N et al. (2017) Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene 36:5709-5721|
|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|
Showing the most recent 10 out of 12 publications