Effect of Melatonin and Linolenic Acid on Mammary Cancer in Transgenic Mice with c-neu Breast Cancer Oncogene

Rao, Ghanta N.; Ney, Elizabeth; Herbert, Ronald A.

doi:10.1023/a:1026552405042

Cited by 41 publications

(25 citation statements)

References 23 publications

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“…In agreement with these results, Rao et al (2000) reported that 4-HPR was unable to decrease the mammary tumor incidence and average tumor weight in transgenic mice bearing c-neu. However, Jinno et al (1999) reported that 4-HPR was able to induce apoptosis in the preneoplastic human mammary epithelial 184-B5/HER cell line bearing high levels of HER2/ neu.…”

Section: Discussionsupporting

confidence: 79%

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

et al. 2003

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The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (Herceptin TM ) led to a sixfold increase in 4-HPR-induced apoptosis in HER2/neuoverexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPRmediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.

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Section: Discussionsupporting

confidence: 79%

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

et al. 2003

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“…The treatment of these transgenic mice with melatonin significantly reduces the incidence of these mammary lesions, the expression of N-ras protein in focal hyperplasic lesions, and the incidence of adenocarcinomas (Mediavilla et al 1997). In transgenic mice expressing the c-neu breast cancer oncogene under the control of an MMTV promoter, melatonin delayed the appearance of palpable tumors and the growth of the tumors (Rao et al 2000).…”

Section: Evidence From In Vivo Studies On Animal Modelsmentioning

confidence: 99%

Melatonin and mammary cancer: a short review.

Sánchez‐Barceló¹,

Cos²,

Fernandez³

et al. 2003

Endocrine-Related Cancer

141

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Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence.In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness; this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and β 1 -integrin.The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERα and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer.

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“…It has anticarcinogenic [Lissoni, 2000;Rao et al, 2000] and free radical scavenging [Qi et al, 2001;Wakatsuki et al, 2001] properties as well.…”

Section: Introductionmentioning

confidence: 99%

GSM modulated radiofrequency radiation does not affect 6‐sulfatoxymelatonin excretion of rats

Bakos

Kubinyi

Sinay

et al. 2003

Bioelectromagnetics

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In this study, the effect of exposure to 900 and 1800 MHz GSM-like radiofrequency radiation upon the urinary 6-sulfatoxymelatonin (6SM) excretion of adult male Wistar rats was studied. Seventy-two rats were used in six independent experiments, three of which were done with 900 MHz and the other three with 1800 MHz. The exposures were performed in a gigahertz transverse electromagnetic mode (GTEM) cell. The power densities of radiation were 100 and 20 microW/cm(2) at 900 and 1800 MHz frequency, respectively. The carrier frequency was modulated with 218 Hz, as in the GSM signal. The animals were exposed for 2 h between 8:00 AM and noon daily during the 14 day exposure period. The urine of rats was collected from 12:00 AM to 8:00 AM, collecting from exposed and control animal groups on alternate days. The urinary 6SM concentration was measured by (125)I radioimmunoassay and was referred to creatinine. The combined results of three experiments done with the same frequency were statistically analyzed. Statistically significant changes in the 6SM excretion of exposed rats (n = 18) compared to control group (n = 18) were not found either at 900 or 1800 MHz.

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Effect of Melatonin and Linolenic Acid on Mammary Cancer in Transgenic Mice with c-neu Breast Cancer Oncogene

Cited by 41 publications

References 23 publications

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

Melatonin and mammary cancer: a short review.

GSM modulated radiofrequency radiation does not affect 6‐sulfatoxymelatonin excretion of rats

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