Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin.
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.
Hill
Steven M
SM
Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Ave, SL-49, New Orleans, LA 70112, USA.
Cheng
Chi
C
Yuan
Lin
L
Mao
Lulu
L
Jockers
Ralf
R
Dauchy
Bob
B
Frasch
Tripp
T
Blask
David E
DE
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000378:metabolism*; D008550:Melatonin / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D010870:Pineal Gland / Q000378:metabolism; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D047628:Estrogen Receptor alpha; D044122:Receptor, Melatonin, MT1; D016211:Transforming Growth Factor alpha; D008550:Melatonin