EUREKA! I think they found it--supressor gene vs her2+ breast cancer!!!!

[Lani]

IF TRUE, YOU MAY BE ABLE TO TEST YOUR DAUGHTERS and if true, they may be able to prevent supression of the suppressor:

1: Cell. 2007 Jun 12; [Epub ahead of print]
FOXP3 Is an X-Linked Breast Cancer Suppressor Gene and an Important Repressor of the HER-2/ErbB2 Oncogene.

Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, Liu Y, Wang Y, Liu X, Chan MW, Liu JQ, Love R, Liu CG, Godfrey V, Shen R, Huang TH, Yang T, Park BK, Wang CY, Zheng P, Liu Y.
Program in Molecular, Cellular, and Developmental Biology and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
PMID: 17570480 [PubMed - as supplied by publisher]


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Lani--very interesting to me, as my brother has a lethal autoimmune disease and I'm HER2 positive. Is there any way to reactive this gene?

[Lani]

Obviously it depends if it was deleted (only by gene therapy whereby a virus or other vector reinserted the gene), or affected by a "functionally significant"
somatic mutation (see below), or downregulated (see below as well).

If downregulated, either inhibit whatever downregulated it or find something which upregulates (stimulates the production of its gene product)

If mutated, either find a way to silence the mutation or otherwise produce/supply the gene product some other way.

I will be reading the full article in more detail.

These things come stepwise--first you have to discover the culprit gene before you can figure out how to "fix" it or substitute for it.

At least it looks as if they are on the way!!!

By the way, what lethal autoimmune disease is it? I will read about what the mice had and see if it sounds similar.

[Lani]

have been reading the article--
the autoimmune disease is called IPEX an acronym for "immune dysregulation, polyendopathy, enteropathy, X-linked"
foxp3 was identified while cloning a gene called scurfin responsible for IPEX in mice and humans
reference:s Bennet et al 2001, Brunkow et al 2001, Chatilla et al 2000, Wildin et al 2001

Hope this helps!

[Bev]

Thanks Lani,

Keep us updated, sounds promising. Bev

[Belinda]

I am so pleased we have you here. Belindaxxxx

[eric]

Lani - I second that motion. Thank you! Eric

[Hopeful]

on Foxp3 after I read this. Seems it is also implicated in Hashimoto's thyroiditis, where the body develops antibodies to the thyroid hormones, an auto-immune disease. There has been a correspondence between this form of thyroid disease and bc, but the link has never been clear. Maybe this is the culprit? I also note that the Foxp3 mutation is on the X chromosome, meaning that mutations for women are inheritable from either parent. My father had prostate cancer, and I think that should have been seen as a bc risk factor for me pre-dx, but never was. Just MO.

Hopeful

[Lani]

same effect per Grace's question to me as to whether there was something one could do to activate the gene(these are all members of what is called the forkhead transcription factors family, it seems):

1: Cancer Res. 2007 Jun 15;67(12):5763-70.
Activation of FOXO3a by the Green Tea Polyphenol Epigallocatechin-3-Gallate Induces Estrogen Receptor {alpha} Expression Reversing Invasive Phenotype of Breast Cancer Cells.

Belguise K, Guo S, Sonenshein GE.
Department of Biochemistry and Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, Massachusetts.
Previously, we showed that the bioactive green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibits growth in soft agar of breast cancer cells with Her-2/neu overexpression. Using gene expression profiling, here we show that EGCG treatment of Her-2/neu-driven mammary tumor cells alters the expression of key regulators in the epithelial to mesenchymal transition (EMT) pathway, reducing invasive phenotype. Specifically, the epithelial genes E-cadherin, gamma-catenin, MTA3, and estrogen receptor alpha (ERalpha) were up-regulated by EGCG, whereas the proinvasive snail gene was down-regulated. Consistently, EGCG inhibited branching colony growth and invasion in Matrigel. EGCG treatment similarly inhibited invasive phenotype of mouse mammary tumor cells driven by Nuclear Factor-kappaB c-Rel and protein kinase CK2, frequently found overexpressed in human breast disease. Recently, we identified the Forkhead box O transcription factor FOXO3a as a major transcriptional regulator of ERalpha. Given the pivotal role of ERalpha in preventing EMT, we hypothesized that the activation of FOXO3a by EGCG plays an important role in the observed reversal of invasive phenotype in ERalpha-positive breast cancer cells. EGCG treatment activated FOXO3a. Ectopic expression of a constitutively active FOXO3a overrode transforming growth factor-beta1-mediated invasive phenotype and induced a more epithelial phenotype, which was dependent on ERalpha expression and signaling. Conversely, a dominant negative FOXO3a reduced epithelial phenotype of ERalpha-low breast cancer cells. These results identify, for the first time, a role for FOXO3a in the inhibition of invasive phenotype in breast cancer cells with active ERalpha signaling and elucidate a novel mechanism whereby EGCG represses EMT of breast cancer cells. [Cancer Res 2007;67(12):5763-70].
PMID: 17575143 [PubMed - in process]

[MJo]

Ay Yi Yi, what does it all mean? I tried to do a little more research, hoping to get easier description. Kept seeing the word inflammation, which worries me, because I've had arthritis for years and have been checked for lupus and MS. Negative, thankfully. Also read that we can't live without Fox3p, just like Her2. Science ladies, what does all this mean?

[Lani]

the her2 gene from making too many of its gene products (like a little kid who you give the job of making ice tea, but instead of making 1 or 2 he/she makes 100--this gene tells the cell/the little kid to stop after 1 or 2 ) When this gene (FOXP3) is missing or mutated, the her2 gene keeps on going like a broken record, cranking out (making) 1 million more her2 receptors(the gene
product) on the outside of EACH breast cancer cell than you would normally have on the outside of a normal breast duct cell or on the outside of most any other lining cell in the body (tear duct lining, airway lining, stomach lining, etc)

This gene is particularly noted in ER+her2+ breast cancer and as I had previously posted an article that her2+ breast cancer can sometimes be hereditary, and had a worse prognosis in the hereditary type than the non-hereditary type and as her2 testing has not been done that long to know if other family members had her2 breast cancer vs other breast cancer, it seems helpful that they are identifying genes which put one at risk for her2+ breast cancer.

Lani--apparently my response to your question, "what auto-immune disease is it?" never made it to the board. He was thought to have scleroderma but has recently been told it's a very severe form of rheumatic arthritis, which runs in our family. So IPEX is definitely not it!

I appreciate your posts and enjoy reading them all, even those that don't apply to my situation. Of course, I'm always looking for that little kernel of information that will make the difference and it's great to have someone like you doing the research for us.

It's much appreciated. Thanks, Grace

[MJo]

Let me add my thanks to Lani for information and also for interpreting when necessary. Five of my great aunts died from breast cancer in their 40s -- maternal and paternal great aunts, both on my mother's side. Even though it skipped my mom's generation, I wonder if there is a gene involved.