Melatonin synergizes with retinoic acid in the prevention and regression of breast cancer

Published on Sunday, 03 November 2013


Breast cancer is the second leasing cause of cancer-related deaths in the United States, and the incidence of and mortality from breast cancer is increasing worldwide. Breast cancer represents approximately 31% of all cancers in women, and current predictions are that one in eight women will develop breast cancer at some during her lifetime. In general, breast cancer is a uniquely endocrine-responsive neoplasm, and over the last two decades, considerable progress has been made in the clinical management of hormone-responsive, estrogen receptor (ER)-positive breast cancer. However, greater than one third of all women who develop metastatic breast cancer do not respond to standard endocrine therapies, and will succumb to the disease. Breast cancer cells, as well as breast epithelial cells, respond to a variety of hormones, including androgens, etsrogens, insulin, progesterone, prolactinic, and retinoic acid, as well as growth factors such as epidermal growth factor (EGF), insuline-like growth factor (IGF-1), an transforming growth factors (TGF) ALPHA e BETA. The growth of endocrine-responsive breast tumours depends heavily on the hormonal milieu presented to the tumor cells and the cross-talk between various signaling pathways activated by the different hormones and growth factors.

Within the last several decades, tremendous advances have been made with respect to the elucidation of the functions of the pineal gland and it major hormone, melatonin (MLT), particularly those relating to photoperiodicity and the regulation of seasonal reproductivity. With the recent cloning of the MLT receptors, we are beginning to define the cellular and molecular mechanism of MLT action. However, advances in our understanding of the pineal gland's impact on human health and disease have been considerably slower. One of the more exciting aspects of current pineal research concerns the role of the pineal gland and, more specifically, MLT's role in neoplastic disease.

The emergence of MLT as an important neuroendocrine regulator of neoplastic growth has stimulated a new phase of research into its mechanism of action at the systemic, cellular and molecular levels. A number of experimental neoplasms have been studied with respect to the ability of MLT and its analogs to influence cancer growth both in vivo and in vitro. These neoplasms include tumors of the breast, prostate, uterus, cervix, ovary, pituitary, skin, neural tissue, lung, liver, colon and connective tissue. However the most studied and one of the more responsive neoplasms to the anti-tumor effect of MLT is breast cancer.



In vivo effects of MLT on Mammary Cancer

Melatonin the major hormonal product of the pineal gland, has repeatedly been shown to exert a negative influence on the development and growth of hormone-responsive breast cancer. Most of the work to date on the oncostatic effects of MLT in vivo has been conducted in the 7,12-dimethylbenzanthracene (DMBA)- and N-nitroso-N-methylurea (NMU)-induced hormone-responsive rat mammary tumor modelsThe DMBA model has been studied with respect to the effects of pinealectomy, photperiod, and MLT administration on the growth and regression of mammary tumors. Blask et al. found that DMBA-induced mammary tumorigenesis is inhibited in light-deprived female rats, and that pinealectomy not only porevent this growth inhibition but actually enhances tumor growth. The advantage of the NMU model aver the DMBA model is that the growth characteristic of the NMU-induced tumors more closely resemble those of human breast cancer cells. The tumor cells of this model are primarily responsive to the mitogenic effects of estrogen, while the tumors in DMBA model are primarily prolactine-responsive. Pinealectomy followed by NMU administration results in enhanced mammary tumor fomration compared to intact controls, and daily late afternoon injections of MLT significantly decreases of latency to onset of the tumors, tumor size, and tumor number. Studies investigating the effects of MLT administered in conjunction with other compounds have also been very promising. Kothari et al. have shown that combined treatment with MLT and the anti-estrogen, tamoxifen, is highly effective in the NMU-induced mammary tumor model in suppressing mammary tumor incidence, and in increasing the latency to onset of tumor appearance.


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