Role of Polyamines in Breast Cancer Growth, Development and Progression

The polyamines putrescine, spermidine, and spermine are small, aliphatic amines that play an important role in multiple cellular functions. Activation of the polyamine pathway is involved in carcinogenesis and other aspects of tumor biology including in breast cancer. Levels of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine biosynthesis as well as the levels of polyamines, are higher in human breast cancer specimens than in normal and benign breast tissue. Inhibition of ODC with alpha-difluromethylornithine exerts a protective effect in the promotion of chemically induced rat mammary tumors as well as in the development of breast cancers in a transgenic model system. Inhibition of polyamine biosynthesis has also been shown to inhibit the growth of hormone-dependent and -independent mammary tumors, both in vitro and in vivo, thus indicating a major role for polyamines in breast cancer cell proliferation. Several lines of evidence indicate that increased ODC activity may contribute to breast cancer progression. Increased tumor ODC activity has been shown to be an independent, adverse prognostic factor for overall survival in women with localized breast cancer. This finding suggests that polyamines may be critically involved in the development of breast cancer metastasis. We have, indeed, observed that administration of DFMO markedly reduced in vitro invasiveness of the hormone-independent MDA-MB-435 and MDA-MB-231 human breast cancer cell lines. More importantly, we have observed that DFMO administration significantly reduced the development of pulmonary metastasis from orthotopically implanted MDA-MB-435 breast cancer xenografts in nude mice. The mechanism of antitumor action of DFMO is currently under active investigation. Several laboratories have shown that inhibition of polyamine biosynthesis results in activation of the MAPK pathway and STAT signaling. We have recently shown that DFMO induced activation of the MAPK pathway in MDA-MB-435 human breast cancer cells is directly involved in the production of the anti-invasive protein, thrombospondin-1. Inhibition of MAPK phosphorylation suppressed DFMO-induced stimulation of thrombospondin-1 and reversed its anti-invasive effect. Collectively, these data indicate that the polyamine pathway may be an attractive target for breast cancer prevention and treatment.