Abstract
Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification.
Highlights
Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer-related death among women[1]
polyoma middle T-antigen transgenic (PyMT) mice and those expressing human apoA-I (PyMT-hApoA-I) were examined for palpable tumours; the first tumours were detected within 50 days
Tumour latency was not affected by hApoA-I expression: T50, defined as the time in which 50% of the animals were free of tumour, was 63 days in PyMT mice and 62 days in PyMT-hApoA-I mice (Fig. 1a)
Summary
Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer-related death among women[1]. Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk[2,3,4]. Inflammation and cancer have been reported to be inter-related[9], the anti-tumourigenic role of apoA-I is currently under investigation. Some studies have demonstrated that human apoA-I-containing HDL has potent anti-tumour activity in xenograft mouse models of ovarian cancer and mouse models of malignant melanoma and Lewis lung carcinoma[10,11]. Recent data have shown that internalization of oxidized low-density lipoprotein (oxLDL) by mammary epithelial cells may play a significant role in breast cancer by triggering a variety of proliferative and pro-inflammatory mechanisms[17]. The potential in vivo therapeutic effect of apoA-I or its mimetics on breast cancer has not been studied. Mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice, which spontaneously develop widespread multifocal adenocarcinomas in the mammary gland, were backcrossed with human apoA-I transgenic mice or administered D-4F, and tumour onset and growth were analyzed
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