Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1−/− mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK’s effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.
The present study examined the role of locus of control and the perceiver 's sex in the estimation of filled and unfilled time intervals. One hundred male and 100 female undergraduates, ranging in age between 16 and 21 years, were administered Collins' I-E Scale followed by a time-estimation task. The latter involved judging 10 time intervals which were either "filled" with a tapping sound presented by the E, or were "unfilled." Results indicate that (a) high internals, compared to low internals, were less likely to overestimate filled intervals, but were more likely to overestimate unfilled intervals, possibly because high internals are more time-conscious; (b) the extent of absolute error in estimation is jointly affected by internality, filled/unfilled intervals, and the perceiver 's sex, but the last-mentioned variable had the most prominent independent effect. In general, males made less error in time estimation than females. It is suggested that the observed sex differences in the present study was probably due to socially learned differences in time consciousness.
#3067 Introduction: The prevalence of obesity in the developed world has reached epidemic proportions in recent years. Obese breast cancer patients exhibit a higher risk for metastasis, larger tumor burden and poorer response to endocrine therapy. Therefore, it is very important to understand the adverse effects of obesity on breast cancer in order to devise appropriate new approaches to their treatment. Obesity is considered an endocrine disorder and serum levels of adiponectin, an adipocytokine proposed to have therapeutic potential, get significantly lowered with obesity. More recently, low serum adiponectin levels were associated with increased risk and more aggressive phenotype (larger tumor size and high histological grade) of breast cancer in women. Recently, anti-proliferative and pro-apoptotic response of adiponectin was shown in breast cancer cells but the molecular mechanisms governing the anti-cancer effects of adiponectin largely remain unknown. In the present study, we found a novel mechanism underlying adiponectin action involving upregulation of tumor suppressor LKB1 and activation of AMPK (AMP-activated protein kinase) signaling to inhibit malignant properties of breast cancer cells.
 Methods and Results: Adiponectin inhibited malignant properties such as invasion and migration of breast cancer cells in matrigel invasion, scratch migration and quantitative Electric Cell-Substrate Impedance Sensing (ECIS) invasion and migration assays. Interestingly, adiponectin induced phosphorylation of AMPK at Thr 172 in breast cancer cells. Adiponectin treatment also affected downstream targets of mTOR signaling pathway, including decreased phosphorylation of p70S6K showing the involvement of mTOR-S6K axis. Intriguingly, we found that adiponectin increased the expression of tumor suppressor LKB1 in breast cancer cells. Co-immunoprecipitation assays revealed that LKB1 co-immunoprecipitated with tumor suppressor TSC2. Increase in expression of upstream kinase LKB1 might directly regulate adiponectin induced activation of AMPK. We also found that breast cancer cells transfected with wild-type LKB1 plasmids increased phosphorylation of AMPK and decreased phosphorylation of p70S6K showing decrease in mTOR activity. In contrast, breast cancer cells transfected with kinase dead LKB1 decreased phosphorylation of AMPK and increased activation of p70S6K.
 Discussion: Taken together these data indicate a novel crosstalk between adiponectin and tumor suppressor LKB1 that modulates AMPK-S6K axis and inhibits metastatic properties, invasion and migration of breast cancer cells. The influence of adipocytokine, adiponectin on breast carcinogenesis is just beginning to be elucidated and our study is the first to show the direct involvement of tumor suppressor genes LKB1 and TSC2 in anti-cancer effects of adiponectin. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3067.
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