Genetic step leading to her2 breast cancer development found

[Christine MH-UK]

I won't even pretend to understand this, but I do find it encouraging that they seem to be making some progress on causes.

'Inefficient proteasomal-degradation pathway stabilizes AP-2alpha and activates HER-2/neu gene in breast cancer.

Li M, Wang Y, Hung MC, Kannan P.

MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA.

HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2alpha protein or its homolog AP-2gamma is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2alpha gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2alpha gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2alpha protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2alpha was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2alpha was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2alpha level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer.'

Thanks Christine.

I do not understand it either -I did a search on AP2, and if it is the same AP2 it links to storage and metabolism of fats in the body which links back to the omega three six balance, ppars, leptin, insulin, inflamatory pathways etc.

All of which without really more than grasping at the shadows links back with all the other stuff I have attempted to grasp to the omega three six balance being a significant factor in HER 2 related cancers.

It is the first time I am truly tempted to pay for access to an article.

RB

[Christine MH-UK]

To me at least (fortunately, I have access to a medical library). I suppose that they will come out with some fancy was of targeting this, but for now I'll just stick with the olive oil.

It was the use of the words "prime cause" that lead me to wonder if they have an understandable explanation for that claim.

I have been reading on fats pathways metabolism cancer etc etc for some months now. There is a great deal simply do not understand at a technical level, but I feel I am beginging to put together some sort of hazy outline.

There clearly are links between HER Fas PPars AP2 leptin......at many levels and often bidirectionally. I had not really taken much notice of AP2 until your post.

Re Olive oil - Olive oil is in there but I still am convinced the three six balance is the real key. ( Olive oil is of course a useful supplement at all sorts of levels)

Thanks

RB

It looks like omega three down regulates AP2 (I presume adipocte P2 is the same thing /family) (perillia is high three). How does that fit in another question but reinforces the existance of linking mechanisms. The question is who is wagging who's tail.



RB


–“ Expression of the late genes of adipocyte differentiation, peroxisome proliferator-activated receptor , adipocyte P2 and adipsin, was significantly (P < 0.05) down-regulated in epididymal fat tissue of rats that had been fed perilla oil rather than beef tallow or olive oil”

Perilla Oil Prevents the Excessive Growth of Visceral Adipose Tissue in Rats by Down-Regulating Adipocyte Differentiation1,2
http://www.nutrition.org/cgi/content...f97996923bcf59

Re olive v n3 discussion and cancer in general terms.

As interesting trial. Poor rats.

RB


Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of ß-carotene and perilla oil in rats
Chihito Komaki, Masataka Okuno, Nobuhito Onogi, Hisataka Moriwaki, Toshihiko Kawamori 1, Takuji Tanaka 1, Hideki Mori 1 and Yasutoshi Muto 2

First Department of Internal Medicine 40 Tsukasa-machi, Gifu 500, Japan
1First Department of Pathology, Gifu University School of Medicine 40 Tsukasa-machi, Gifu 500, Japan

2To whom correspondence should be addressed

The modulating effect of the combined dietary feeding of ß-carotene and perilla oil, which is rich in {alpha}- olinolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. Rats received oral administration of ß-carotene (0, 50 or 200 mg/kg body weight/day) and fed a basal diet containing either 12% olive oil, 3% perilla oil plus 9% olive oil, or 12% perilla oil. A dose-dependent suppressive effect of perilla oil was found. The numbers of ACF were 42.0 and 18.4% of those of the 12% olive oil-fed controls in the rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively. The development of ACF was also reduced significantly by the addition of dietary ß-carotene in each of the oil-fed groups (P < 0.05, respectively). The suppression by the combination of ß-carotene and perilla oil was synergistic, as the numbers of ACF were 12.9 and 8.9% of those of the 12% olive oil-fed controls in ß-carotene-treated rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively. P-Carotene plus perilla oil also suppressed the numbers of silver-stained nucleolar organizer regions and the expression of ras mRNA in the colonic mucosa (cell proliferation biomarkers). Following administration of ß-carotene, a significant increase in the concentration of intact ß-carotene molecules was found in the colonic mucosa, livers, and sera. However, no accumulation of retinoids was observed in the colonic mucosa, suggesting that the inhibitory effect may not be related to the provitamin A activity. These results suggest that the combination of ß-carotene and perilla oil may be useful in the prevention of colon cancer.