Amitabha Ray

Adipokine leptin in obesity-related pathology of breast cancer.

Breast cancer is one of the most common cancers and a leading cause of cancer death in women worldwide. Incidences of breast cancer are substantially higher among postmenopausal than premenopausal women. Obesity is a common risk factor for postmenopausal breast cancer. For the development of postmenopausal breast cancer, several phenomena may function in relation with obesity. It is well known that adipose tissue is the major source of oestrogens in postmenopausal women, and oestrogens are associated with the pathological process of breast cancer. The enzyme aromatase (CYP19), present in the adipose tissue, catalyses the conversion of oestrone from androstenedione, which is mainly produced in the adrenal gland under the influence of adrenocorticotropic hormone. As the rate of oestrogen production is related to the amount of the adipose tissue, the quantity of body fat could be a significant source of oestrogens. Furthermore, there is an inverse association between obesity and circulating levels of sex hormone-binding globulin (SHBG), the principal carrier protein for oestrogen. Lower levels of SHBG increase the free or unbound form of oestrogen in blood, and unbound oestrogens may elevate the risk of breast cancer. Interestingly, a conflicting relationship exists between obesity and breast cancer prognosis. It has been documented that obesity is involved with the pathogenesis of oestrogen receptor-positive (ER+) breast cancer, which usually has a better prognosis than ER− breast cancer. On the other hand, obese women with breast cancer have been found to have a poor prognosis. Consequently some important factors other than the oestrogens may be crucial in the mechanisms by which obesity influences the prognosis of breast cancer. Evidence about the importance of insulin, insulin-like growth factors (IGFs) and leptin is accumulating in this complicated pathological phenomenon (Stephenson and Rose 2003; McTiernan 2005; Goodwin et al. 2012). Systemic low-grade inflammation and insulin resistance are two related mechanisms that have been hypothesized to play a role in the obesity–disease associations. In insulin resistance, serum levels of insulin and IGFs are elevated and the insulin/IGF-I signalling is altered (Probst-Hensch 2010). Furthermore, adipose tissue can act like an endocrine organ, releasing several hormone-like cytokines (adipokines) such as leptin, resistin and adiponectin. The majority of these adipokines, including leptin, participates in the pro-inflammatory processes in obesity and perpetuates the state of insulin resistance. A recent report on breast cancer observed higher expression of leptin and its receptors (Ob-R) at the lesion site in patients with insulin resistance (Carroll et al. 2011). On the other hand, adiponectin is an antiinflammatory adipokine, and a growing body of evidence suggests its anti-cancer effects (Grossmann et al. 2008a; Cleary et al. 2010) (table 1). This review briefly discusses relevant current findings on leptin biology and breast cancer as well as approaches to modulate the deleterious effects of this adipokine.

Immunomodulatory effects of anti-estrogenic drugs

Immunomodulatory effects of anti-estrogenic drugs There are substantial experimental, epidemiological and clinical evidences that show that breast cancer pathology is influenced by endogenous estrogens. This knowledge is the foundation upon which endocrine deprivation therapy has been developed as a major modality for the management of breast cancer. Tamoxifen, which functions as a competitive partial agonist-inhibitor of estrogen at its receptor, has been widely used for more than three decades for adjuvant endocrine treatment in breast cancer. Currently, other effective drugs for endocrine therapy include raloxifene, different aromatase inhibitors (particularly third-generation agents) and luteinizing hormone-releasing hormone agonists. In recent years, a growing body of evidence suggests that these drugs can also act as immune modulators by altering the function of various leukocytes and the release of different cytokines. Moreover, there is evidence that anti-estrogens may prove to be beneficial in the treatment or prevention of some autoimmune diseases due to their effects on immune function. However, their immunopharmacological aspects in the present state of knowledge are not precisely comprehensible. Only a clear pathophysiological understanding could lead to an efficient strategy for breast cancer prevention and decrease in the mortality due to this disease. Imunomodulatorni učinak antiestrogenih lijekova Postoje značajni eksperimentalni, epidemiološki i klinički dokazi da na patologiju karcinoma dojke utječu endogeni hormoni. Zbog toga je snižavanje razine hormona najvaž niji način terapije ove bolesti. Već više od tri dekade koristi se tamoksifen, kompetitivni parcijalni agonist-inhibitor receptora za estrogene. U suvremenoj terapiji koriste se još raloksifen, različiti inhibitori aromataze (posebno treća generacija inhibitora) i agonisti hormona za oslobađanje luteinizirajućeg hormona. U posljednje vrijeme sve više činjenica ukazuje na to da ti lijekovi imaju i imunomodulatorni učinak, tj. utječu na funkciju leukocita i oslobađanje različitih citokina. štoviše, postoje dokazi da antiestrogeni lijekovi imaju povoljni učinak na neke autoimune bolesti. Međutim, njihov imunofarmakološ ki učinak nije do kraja objašnjen. Samo potpuno razumijevanje patofizioloških procesa može uroditi učinkovitom strategijom za prevenciju i terapiju te smanjenje mortaliteta od karcinoma dojke.

Extracellular matrix in obesity - cancer interactions.

Abstract Obesity or overweight is a risk factor for several health disorders such as type 2 diabetes, hypertension, and certain cancers. Furthermore, obesity affects almost all body systems including the extracellular matrix (ECM) by generating a pro-inflammatory environment, which are associated with abnormal secretions of several cytokines or hormonal substances, for example, insulin-like growth factors (IGFs), leptin, and sex hormones. These chemical mediators most likely have a great impact on the ECM. Accumulating evidence suggests that both obesity and ECM can influence tumor growth and progression through a number of chemical mediators. Conversely, cells in the connective tissue, namely fibroblasts and macrophages, support and aggravate the inflammatory situation in obesity by releasing several cytokines or growth factors such as vascular endothelial growth factor, epidermal growth factor, and transforming growth factor-beta (TGF-β). A wide range of functions are performed by TGF-β in normal health and pathological conditions including tumorigenesis. Breast cancer in postmenopausal women is a classic example of obesity-related cancer wherein several of these conditions, for example, higher levels of pro-inflammatory cytokines, impairment in the regulation of estrogen and growth factors, and dysregulation of different ECM components may favor the neoplastic process. Aberrant expressions of ECM components such as matrix metalloproteinases or matricellular proteins in both obesity and cancer have been reported by many studies. Nonstructural matricellular proteins, viz., thrombospondins, secreted protein acidic and rich in cysteine (SPARC), and Cyr61-CTGF-Nov (CCN), which function as modulators of cell-ECM interactions, exhibit protean behavior in cancer. Precise understanding of ECM biology can provide potential therapeutic targets to combat obesity-related pathologies.

Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer.

OBJECTIVES The purpose of this study was to evaluate the level of expression of the BRCA1 and BRCA2 proteins in sporadic breast cancer cases to determine the functional role of these genes in breast carcinogenesis. MATERIALS AND METHODS Paraffin embedded histologically proven invasive breast tissue sections that were obtained from 40 patients and the adjacent normal breast tissue sections used as controls to determine breast carcinoma specific changes in the expression of BRCA1 and BRCA2 by immunohistochemistry (IHC). RESULTS Majority of the cases express either low or no detectable level of BRCA1 expression in tumor tissues in comparison with control; the decline in BRCA1 expression was found to be more prominent in advanced grade 3 disease. On the other hand, the expression of BRCA2 protein was moderate or low in breast cancer cases and its overall distribution did not show significant difference when compared with controls. Interestingly, those breast cancer cases, which were found to express low or no BRCA1 expression, demonstrated a higher protein level of BRCA2. The inverse correlation of BRCA1 and BRCA2 expression was more prominent in post-menopausal patients. CONCLUSIONS Our results demonstrate in a subset of cases that decline in BRCA1 expression that may be associated with potentially compensatory increase in BRCA2 protein, which may depend on tumor grade as well as menopausal status.

Pathobiology of cancer and clinical biochemistry

Early diagnosis of cancer clearly reduces morbidity and mortality, and a sizable number of cancers could be prevented at the secondary level with appropriate diagnostic tools. In early detection, biochemical analyses are highly supportive of the cytological and/or histopathological assessments. Among children, cancers probably originate from altered signaling pathways attributable to developmental genetic disorders. In adults, generally preventable risk factors, e.g., cigarette smoking, infections, unhealthy lifestyle and obesity, create a state of inflammation and associated oxidative imbalance, which may progress to ma- lignancy. Pathological mechanisms of cancer are associated with abnormal expressions of various endogenous molecules that can be used as tumor biomarkers. Evaluation of such markers in different phases along the disease course plays a crucial role in clinical management and prognosis. Definitely, the current trend of active research on neoplastic mechanisms will help the clinical biochemistry laboratories to provide a better service.

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Abstract Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

Abstract 5540: CCN5/WISP-2 prevents leptin-induced breast cancer cell growth and migration

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL In menopausal women, one of the important risk factors for breast cancer is obesity/adiposity. Despite multiple studies, the biological mechanism by which obesity influences the breast carcinogenic process is still unclear. It is evident from various studies that leptin, a 16 kDa protein hormone over produced in obese people, plays a critical role in neovascularization and tumorigenesis in breast and other organs. Present studies demonstrate that leptin is able to induce proliferation and migration of estrogen receptor positive MCF-7 and ZR-75-1 breast tumor cell lines in a dose-dependent fashion but these effects are minimal in ER-negative MDA-MB-231 cells. Additionally, these studies found that leptin suppresses the transcriptional activation of anti-invasive gene CCN5/WISP-2. Although the suppression of CCN5 has no impact on the constitutive proliferation of these cells, it is critical for leptin-induced proliferation and necessary for the induction of in vitro migration of these cells because the addition of CCN5 recombinant protein into the media markedly inhibits the leptin-induced proliferation and migration. Collectively, these in vitro studies suggest that CCN5 may serve as a gatekeeper for leptin dependent breast carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2011-5540