Interfering Role of ERα on Adiponectin Action in Breast Cancer

Abstract

Obesity is characterized by an excess of adipose tissue, due to adipocyte hypertrophy and hyperplasia. Adipose tissue is an endocrine organ producing many bioactive molecules, called adipokines. During obesity, dysfunctional adipocytes alter adipokine secretion, contributing to pathophysiology of obesity-associated diseases, including metabolic syndrome, type 2-diabetes, cardiovascular diseases and many types of malignancies. Circulating adiponectin levels are inversely correlated with BMI, thus adiponectin concentrations are lower in obese than normal-weight subjects. Many clinical investigations highlight that low adiponectin levels represent a serious risk factor in breast carcinogenesis, and are associated with the development of more aggressive phenotype. A large-scale meta-analysis suggests that BMI was positively associated with breast cancer mortality in women with ERα-positive disease, regardless menopausal status. This suggests the importance of estrogen signaling contribution in breast tumorigenesis of obese patients. It has been largely demonstrated that adiponectin exerts a protective role in ERα-negative cells, promoting anti-proliferative and pro-apoptotic effects, while controversial data have been reported in ERα-positive cells. Indeed, emerging data provide evidences that adiponectin in obese patients behave as growth factor in ERα-positive breast cancer cells. This addresses how ERα signaling interference may enhance the potential inhibitory threshold of adiponectin in ERα-positive cells. Thus, we may reasonably speculate that the relatively low adiponectin concentrations could be still not adequate to elicit, in ERα-positive breast cancer cells, the same inhibitory effects observed in ERα-negative cells. In the present review we will focus on the molecular mechanisms through which adiponectin affects breast cancer cell behavior in relationship to ERα expression.

Nutrition in Cancer Therapy in the Elderly—An Epigenetic Connection?

“…However, steroids and hormonal therapy in a long-term cancer treatment may stimulate the development of diabetes and cardiovascular disease at which older adults, especially with obesity, are at risk [31,32]. Therefore, nutritional research is needed among obese older cancer patients to establish prognosis of the disease course [33].…”

Adiponectin as a Potential Biomarker for Pregnancy Disorders

“…Adiponectin, also known as an adipocyte complement-related protein of 30 kDa (Acrp30), was first discovered in 1995 [ 16 ], while three other independent research groups also identified adiponectin as AdipoQ [ 17 ], adipose most abundant gene transcript 1 (apM1) [ 18 ] and gelatin-binding protein of 28 kDa (GBP-28) [ 19 ] using different approaches. Human adiponectin is a 244 amino acid protein that consists of an amino (NH2)-terminal signal sequence, a variable region, a collagenous domain and a carboxy (COOH)-terminal globular domain ( Figure 2 ) [ 16 , 20 , 21 ]. Adipocytes secrete adiponectin into the bloodstream as three oligomeric complexes, including a low-molecular-weight (LMW) trimer (~60 kDa), a medium-molecular-weight (MMW) hexamer (~150 kDa), and a high-molecular-weight (HMW) multimer (~420 kDa), which are formed via a series of complex signalling and modification processes [ 20 , 21 ].…”

“…Human adiponectin is a 244 amino acid protein that consists of an amino (NH2)-terminal signal sequence, a variable region, a collagenous domain and a carboxy (COOH)-terminal globular domain ( Figure 2 ) [ 16 , 20 , 21 ]. Adipocytes secrete adiponectin into the bloodstream as three oligomeric complexes, including a low-molecular-weight (LMW) trimer (~60 kDa), a medium-molecular-weight (MMW) hexamer (~150 kDa), and a high-molecular-weight (HMW) multimer (~420 kDa), which are formed via a series of complex signalling and modification processes [ 20 , 21 ]. In its simplest form, adiponectin is a trimer, consisting of three monomers (~28 kDa) that undergo post-translational modifications (hydroxylation and subsequent glycosylation), and is stabilized by disulphide bonds within the collagenous domains of each monomer [ 20 , 22 ].…”

“…The trimers further multimerize via disulphide bonds at their collagenous domains to form hexamers and multimers, which are comprised of 12–32 monomers [ 20 , 22 ]. Globular adiponectin, which is synthesized by proteolytic cleavage of full-length adiponectin at the globular domain is also present at low levels in human plasma and is biologically active [ 21 , 22 , 23 ], while the monomeric form of adiponectin is undetected in the circulation and is restricted to adipocytes [ 24 , 25 ].…”

Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity

“…AMPK contributes to insulin sensitivity due to an increase in glucose uptake in insulin sensitive organs, but, unlike leptin, adiponectin is reduced in obese subjects, thus its anti-inflammatory, anti-proliferative and pro-apoptotic effects are compromised in this population [ 127 ]. Solid tumours present adiponectin receptors [ 128 ] and studies with MCF-7 human breast cancer have indicated positive apoptotic response effects via p53 are modulated by AMPK phosphorylation induced by adiponectin [ 129 , 130 ] specially in ERα negative cancer [ 130 , 131 , 132 ]. Besides that, adiponectin is able to inhibit the activity of an enzyme responsible for estrogen production, aromatase, one of the major risk factors for breast cancer development in postmenopausal women [ 90 ].…”