Age-Related Decline in Melatonin and Its MT1 Receptor Are Associated with Decreased Sensitivity to Melatonin and Enhanced Mammary Tumor Growth
Steven M. Hill,
David E. Blask.
The pineal hormone melatonin (MLT) has potent anti-breast cancer activity, its actions are heavily mediated
via the MT1 receptor and subsequent modulation of downstream signaling pathways including cAMP/PKA, Erk/MAPK,
p38, and Ca2+/calmodulin. Also, via the MT1 pathway, MLT can repress the transcriptional activity of some mitogenic
nuclear receptors including ERα, GR, and RORα, while potentiating the activity of other receptors (RARα and RXRα)
involved in differentiation, anti-proliferation, and apoptosis. A review of the literature supports the view that MLT, via its
MT1 receptor, can suppress all phases of breast cancer including initiation, promotion, and progression. During the fifth
and sixth decades of life, the production of MLT diminishes, concurrently with an increase in the incidence of breast cancer.
Inasmuch as MLT has been demonstrated to have anti-cancer activity, we hypothesized that there may be a causal
link between the reduction in MLT production in the pineal gland and the incidence of breast cancer which increases with
age. We designed this study to establish whether a truly inverse relationship exists between tissue-isolated mammary tumor
growth in young (2 months), adult (12 months), and old (20 months) female Buffalo rats and the decrease in both
MLT and the MT1 receptor with age, such that a causal link could be found. Serum MLT levels were measured in both
the light and dark phases. A significant 29% decrease in serum MLT levels, measured at the nocturnal peak, was found
in the adult and senescent rats (75% decrease) in comparison to that in young rats. In young rats, the nocturnal pineal
gland MLT content exceeded daytime levels by 19-fold compared to a sevenfold increase in old mice. Also, the MT1 receptor
was found to be significantly lower in the nighttime and early morning in the senescent rat uterus as compared
to uteri from young and adult rats. Analysis of the rate of growth in transplanted, tissue-isolated, mammary tumors induced
by N-nitroso-n-methyl-urea (NMU) showed a significant increase in the senescent rats, but not in the young or adult
rats Additionally, diminished response to the inhibitory action on tumor growth of exogenous MLT was noted in senescent
rats such that tumor growth was suppressed by only 33% compared to 48% and 66% in adult and young rats, respectively.
The diminution of the response of tumors to exogenous MLT was found to correlate with reduced MT1 receptor
expression in senescent compared to young and adult rats. These data suggest that the observed age-associated enhanced
growth of tumors is related to the much reduced levels of MLT and its receptor in aged animals which reduce the sensitivity
of tumors to inhibition by exogenous MLT.
Keywords: Aging, breast cancer, circadian rhythms, light at night, mammary tumor, melatonin, MT1 receptor, pineal gland,
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