RETRACTED ARTICLE: Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin

Abstract

Serum melatonin (MLT) levels have been reported to diminish significantly by the 5th and 6th decades of life as the incidence of breast cancer increases. Given MLT's anti-cancer activity, we hypothesize that age-related decline in pineal MLT production leads to enhanced breast cancer development and growth as women age. In this study, we sought to determine whether the growth of tissue-isolated mammary tumors in young, adult, and old female Buffalo rats relates to the age-related changes in MLT and its MT1 receptor. Significant decreases in the peak nighttime serum MLT levels were observed in old as compared to adult and young rats. Significantly diminished nighttime and early morning levels of MT1-melatonin receptors were observed in uteri from old rats compared to adult and young rats. Growth rates in transplanted, tissue-isolated, carcinogen-induced mammary tumors are significantly increased in old rats as compared to adult or young rats. The growth-suppressive actions of exogenous MLT are diminished in old rats compared to adult and young rats. This decrease in tumor response correlates with reduced expression of the MT1 receptor in old as compared to young and adult rats. Thus, enhanced mammary tumor growth is associated with old age and diminished levels of MLT and MT1 receptor during old age, resulting in reduced sensitivity to exogenous MLT. Finally, our studies demonstrate that the tissue-isolated tumor model is viable model system in which to study the role of aging on breast cancer growth.

Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

“…A recent cohort study of postmenopausal women has also revealed that an increased concentration of urinary 6-sulfatoxymelatonin (aMT6s), the major metabolite of MLT, is statistically significantly associated with a lower risk of developing breast cancer [9]. These observations are further supported by the fact that MLT production gradually declines with advancing age, with MLT levels reported to be low in elderly individuals, associated with ER-positive breast cancer and linked with enhanced tumor growth in rats [10][11][12].…”

Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium

“…Since Ca 2 þ seems to be a crucial regulator of the cell cycle necessary for proper proliferation (Bertolesi et al, 2002;Gray et al, 2004;Naziroğlu et al, 2012;Wang et al, 2000), the associated reduction of free [Ca 2 þ ] i observed in our experiments supports the clue that melatonin may contribute to the decline of proliferation also disturbing internal Ca 2 þ homeostasis. The G-protein-coupled melatonin MT1 receptors are expressed in MCF-7 cells (Girgert et al, 2009;Hill et al, 2011b;Jablonska et al, 2013;Jawed et al, 2007;Rich et al, 1999) and, via the inhibition of adenylate cyclase activity (Jablonska et al, 2013;Jawed et al, 2007), their activation leads to the decrease of adenosine 3 0 , 5 0 -cyclic monophosphate (cAMP) synthesis. Considering that in MCF-7 melatonin affected cell functionality by a significant depletion of ATP levels (Margheri et al, 2012), we propose that the decrease of cAMP, leading to a decrease of PKA activity and channel phosphorylation, can be considered a crucial mechanism involved in the reduction of L-and T-type Ca 2 þ currents (Mahapatra et al, 2012;Novara et al, 2004;Sundelacruz et al, 2009), further stressing the evidence that Ca 2 þ channels are a target by which melatonin can modulate cell proliferation.…”

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

“…Understanding the health-relevant impact of LAN on L1 activity in normal cells is an important next step in our research, as it is directly relevant to aging and age-associated diseases. It is established that melatonin production and its receptor expression decline with age, 63 suggesting the possibility of an increase in L1-induced damage with age. As previously mentioned, genomic instability is an underlying cause of most cancers.…”