Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: Role of menopausal status, estrogens and hyperglycemia

Abstract

The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such ''adipose milieu'' is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or ''adipogenotoxicosis.'' We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFa and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by 3 H 2 O release from 3 H-1b-androstenedione. In the postmenopausal BC patients, NO and TNFa production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre-and postmenopausal BC patients. This condition is likely being maintained through estrogen-and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis. ' 2007 Wiley-Liss, Inc.

Endocrinology of the Wild and Mutant Brca1 Gene and Types of Hormonal Carcinogenesis

“…The latter may involve not only estrogens but also peptide factors, for example, activated IGF-1 system. The condition observed upon 'transfer' from the wild-type to a mutant BRCA1 may be designated as endocrine genotoxic liberation (Figure 2), which makes it possible to regard BRCA1 as another modulator of endocrine-genotoxic switchings (EGS) described by this author elsewhere [89,90,91].…”

“…When the mammary adipose tissue of breast cancer patients is taken as an example, it is noted that the genotoxic shift is promoted by local (tumor proximity, fat content in mammary gland) as well as systemic (impaired tolerance to glucose) and, also, external factors (smoking) [90]. It cannot be ruled out that similar modulating influences may be produced by some genetic factors, as is aptly exemplified by the changing of the wild-type BRCA1 into its mutant forms or by its knocking down.…”

“…Similarly, the effects of classic estrogens may be modified by some xenoestrogens, for example, during fetal development [93,94]. Two other endocrine-genotoxic switches involve the phenomena of Janus (dual) function of glucose (that is, its abilities to simultaneously induce insulin secretion and ROS generation, which may differ individually, meaning from person to person) and adipogenotoxicosis (a shift in the ratio of genotoxic and hormonal properties of adipose tissue) [89,90] and may produce similar effects on tumor biology. The three switchings in estrogen, glucose and adipose tissue 'systems' may act independently or in concert and, together with their inducers, may be the targets for the prevention and, likely, the treatment of the main noncommunicable diseases including cancer.…”

Effects of Dietary Restriction on Cancer Development and Progression

“…Interestingly, in a tumor mass, malignant cells are strictly connected with the socalled "cancer-associated adipocytes" (CAAs) and interact with them (Calle and Kaaks 2004). In particular, CAAs show the reduction of peculiar markers including HSL, APN, and resistin, and increased proinflammatory cytokine expression such as IL-6 and IL-1β and TNF-α (Berstein et al 2007;Ribeiro et al 2012;Dirat et al 2011). This altered expression, associated with the production of adipokines, results in a tumor microenvironment variation that favors uncontrolled growth.…”

Dietary restriction: could it be considered as speed bump on tumor progression road?

“…Adipocytes localized near the tumor mass are called Bcancer-associated adipocytes^and show a reduction of adipose markers, such as HSL, APN, and resistin, and an increased expression of inflammatory cytokines (e.g., IL-6 and IL-1β) [61]. Adipocytes play an important role in cancer progression and may contribute to carcinogenesis and tumor invasiveness, since they are a source of pro-inflammatory cytokines, such as IL-6 and TNF-α, ROS, and matrix metalloproteases [62][63][64][65]. Moreover, adipocytes are able to secrete adipokines that increase angiogenesis, fibrosis, and inflammation by recruiting macrophages and endothelial cells inside the cancer microenvironment in a way mediated by NF-KB [66].…”