Ornithine decarboxylase activity, prolactin blood levels, and estradiol and progesterone receptors in human breast cancer

Glikman, Patricia; Vegh, Irene; Pollina, María Angélica; Mosto, A; Levy, Carlos

doi:10.1002/1097-0142(19871101)60:9<2237::aid-cncr2820600923>3.0.co;2-j

Cited by 33 publications

(16 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7). Of clinical relevance, increased ODC activity in primary tumors has been found to be associated with adverse prognostic features (8,9). More importantly, we (10) and subsequently other investigators (9) have shown that high tumor ODC activity is an independent, adverse prognostic factor for disease-free and overall survival in patients with localized breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Among the multiple effects of DFMO we have shown that induction of MAPK activation is instrumental in its antiinvasive action since the anti-invasive effects of the drug could be reversed with the MEK inhibitor PD98059 (5). Furthermore, we have shown that DFMO-induced MAPK activation is causally linked to upregulation of TSP-1 (5), an extracellular matrix glycoprotein with tumor suppressive and antimetastatic activity primarily resulting from its potent anti-angiogenic effect (6)(7)(8)(9). Because of its possible role as mediator of the anti-metastatic effect of DFMO in breast cancer, we deemed it important to investigate the mechanisms of regulation of TSP-1 production by DFMO under both in vitro and in vivo conditions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells

Manni

Rager

Kimball³

et al. 2007

Int J Oncol

View full text Add to dashboard Cite

Abstract. We have previously observed that inhibition of polyamine biosynthesis with α-difluoromethylornithine (DFMO) upregulates production of thrombospondin-1 (TSP-1), an extracellular matrix protein with potent anti-angiogenic and antimetastatic properties, by MDA-MB-435 human breast cancer cells in culture. The present experiments were designed to investigate the mechanisms by which DFMO regulates TSP-1 production in this system. 35 S-methionine pulse chase experiments indicated that DFMO administration increased TSP-1 synthesis by approximately 6-fold, while it slightly but significantly decreased protein half-life from 35 to 28 min. DFMO treatment increased steady state TSP-1 mRNA levels by 2-fold in MDA-MB-435 cells. TSP-1 promoter reporter studies indicated that this increase was largely due to activation of transcription. Analysis of distribution of TSP-1 mRNA levels between non-polysomal, subpolysomal and polysomal fractions in control and DFMO-treated cells suggested a major stimulatory effect of the drug on TSP-1 translation. A similar increase in TSP-1 transcription and translation in response to DFMO treatment was also observed in vivo in MDA-MB-435 breast cancer xenografts. Surprisingly however, we failed to detect an increase in TSP-1 protein as assessed by Western blot analysis. The reason for this unexpected finding is unknown but may be due to DFMO-induced stimulation of TSP-1 secretion into the systemic circulation, thus preventing its accumulation within the tumor.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells

Manni

Rager

Kimball³

et al. 2007

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…Using an experimental system of mammary tumor progression, we found that an increase in cellular ODC activity was associated with transition to hormone independence as well as to a less differentiated and more metastatic phenotype [52]. With respect to human breast cancer, increased ODC activity has been shown to be associated with adverse prognostic features such as high cellularity, low histological differentiation, high nuclear aplasia, peritumoral lymphatic and blood vessel invasion, high S-phase fraction, and cathepsin-D expression [15,53]. In a pilot study involving a cohort of 50 primary human breast cancers, we have observed that ODC activity was a strong negative independent prognostic factor of overall survival [54].…”

Section: Polyamines and Tumor Progressionmentioning

confidence: 99%

Role of Polyamines in Breast Cancer Growth, Development and Progression

Manni¹

2005

CCTR

View full text Add to dashboard Cite

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 -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.

show abstract

“…ODC becomes activated after treatment with chemical carcinogens and tumor promoters, as well as in cells transformed by various oncogenes such as v-src, neu and ras. [6][7][8] The level of ODC was reportedly elevated in various cancers [9][10][11] and related to recurrence. 12 Some chemotherapeutic agents, such as DFMO, which aimed to inhibit the activity of ODC have appeared and taken on inhibitory effects on tumor growth in vitro and in vivo, 13,14 although showing dose-limiting toxicity.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effect of antisense ODC adenovirus on human prostate cancer cells

Zhang

Liu

Zhang

et al. 2005

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

Ornithine decarboxylase (ODC), the first enzyme of polyamine biosynthesis, was found to increase in cancer cells, especially prostate cancers. Some chemotherapeutic agents aimed to decrease ODC expression showed inhibitory effects on cancer cells. In this study, we examined the effect of adenoviraltransduced antisense ODC on prostate cancer cells. An adenovirus carrying antisense ODC (rAd-ODC/Ex3as) was infected to prostate cancer cells PC-3 and LNCap. Expression of ODC and concentration of polyamines in cells were determined by Western blotting and HPLC. MTT (3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay was used to analyze the effect on cell growth. Cell cycle was evaluated by FCM and cellular invasion by Matrigel invasion assay. A nude mouse xenograft model was used to examine tumorigenicity. Expression of ODC in PC-3 and LNCap cells were reduced to 45 and 59%, and three polyamines were also decreased by the rAd-ODC/Ex3as treatment. Consequently, cell growth was substantially inhibited and cell cycle arrested at G1 phase. Matrigel invasion assay showed relatively low invasion. Marked suppression of tumor formation was observed in the xenograft model. This study suggests that rAd-ODC/Ex3as has the antitumor effect on the human prostate cancer cells.

show abstract

Ornithine decarboxylase activity, prolactin blood levels, and estradiol and progesterone receptors in human breast cancer

Cited by 33 publications

References 22 publications

Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells

Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells

Role of Polyamines in Breast Cancer Growth, Development and Progression

Antitumor effect of antisense ODC adenovirus on human prostate cancer cells

Contact Info

Product

Resources

About