Inheriting HER2+ ???

[Joanne S]

Per: http://www.herceptin.com/herceptin/patient/testing/her2.jsp (http://www.herceptin.com/herceptin/patient/testing/her2.jsp)

Your tumor's HER2 status is not hereditary.

This means that HER2 status is not passed down from your parents, and you can't pass it on to your children.


HER2-overexpressing means:
there is too much HER2 protein/receptor on the surface of the cancer cells.


HER2/neu-positive breast cancer,
HER2-overexpressing breast cancer,
HER2+ breast cancer
are exactly the same.

[Lani]

if you place familial her2 into the search you may find more postings but I will provide you with two below that I have found most interesting:

if I can't copy and paste well they may be placed as separate posts.

[Lani]

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

[Lani]

Am J Clin Pathol. 2003 Dec;120(6):917-27. Links
Her-2/neu gene amplification in familial vs sporadic breast cancer. Impact on the behavior of the disease.

Espinosa AB, Tabernero MD, GarcÃ*a-MacÃ*as MC, Primo D, Bernal AG, Cruz JJ, Ramos M, Font de Mora J, Gómez Alonso A, Orfao A.
Cancer Research Center, Department of Medicine, General Cytometry Service, University of Salamanca, Salamanca, Spain.
We compared the incidence of Her-2/neu amplification in patients with and without a family history of breast cancer and correlated gene status with clinicobiologic and prognostic features in sporadic and familial cases. Of 108 patients, 28.7% had gene amplification. Among 96 cases with family history information available, 28 had an affected first-degree relative. The gene was amplified more frequently in familial than in sporadic cases (13/28 [46%] vs 14/68 [21%]; P = .01). Among familial cases, amplification was associated with adverse clinicobiologic features (poorly differentiated tumors [P = .05], larger tumors [P = .05], more lymph nodes involved [P = .04], and DNA aneuploid [P = .02] and highly proliferative tumors [P = .005]), and the relapse (P = .02) and disease-related death (P = .05) rates were higher than in cases without amplification. Among sporadic cases, amplification was not associated with significantly different disease features, except for a higher incidence of DNA aneuploid tumors (P = .01), percentage of S-phase tumor cells (P = .006), and lower proportion of estrogen (P = .001) and progesterone (P = .002) receptors. Her-2/neu amplification was observed more frequently among patients with a family history of breast cancer, in whom it was associated with adverse clinicobiologic features and a worse clinical outcome.
PMID: 14671981 [PubMed - indexed for MEDLINE]

[Joanne S]

You cannot inherit HER2. It is not Hereditary:
I agree the information I posted from herceptin.com site is simplified. And it's straight forward.


Lani,

Honestly, I am pretty ignorant to your two posts.---they are really over my head.

I don't see anywhere (or maybe just don't understand) where either post implies that Her2+ is hereditary.

My simplified drift on your posts
-HER2 is more apt to show up in first degree family members (than in sporadic cases) in familial cases that have specific features (poorly differentiated tumors, large tumors, more lymph involve....lots of other clinicobiologic features....)
-FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene? All I get out of this is that FOXP3 has an impact on HER2 amplification. This entire post is over my head.
-"IF TRUE, YOU MAY BE ABLE TO TEST YOUR DAUGHTERS and
if true, they may be able to prevent supression of the suppressor." Your comment totally confused me????

I appreciate your input. I mean no disrespect to you nor am I challenging you. Just seeking clarification. I tend to stick with the more easy to understand simplied facts regarding what's currently available and going on now (less about trials and studies). I'm pretty simple minded.

Sincerely.

[Lani]

as that her2+ bc is or is not heritable are all oversimplifications as we do not understand it well enough to draw such absolute conclusions. There are some who feel every tumor in every patient is different from every tumor in every other patient, but there is so much heterogeneity in her2+ breast cancer that even those who are trying to divide breast cancer into molecular subtypes based on genes over and underexpressed based on microarray analysis separate those that are her2+ER- and are unsure where to classify those that are her2+ER+ and think that some her2+ER- do not belong with the rest.

Just as one should not lump all breast cancer together as it does not all respond the same to the same treatments (sometiing which has been done in the past as they did not have the knowledge to separate out those types which behaved differently and needed different treatments) lumping all her2+ breast cancers together and deciding whether or not they are hereditary, or respond to green tea derivatives or metastasize to the brain only after metastasizing elsewhere or other generalizations assume we understand the disease and its subtypes better than we do.

Some her2+ breast cancers are BRCA2+ (not many, but some are) and those appear inheritable. Some Her2+ (especially ER+) breast cancers
may be due to FOXP3 but we have no data yet as to how many of them are.

Until research money and interest are spent on retrieving old pathologic specimens of the affected relatives of her2+ breast cancer patients and going back and measuring her2 levels, this will be very difficult to figure out.

At a June conference on the Biological Basis of Breast Cancer I asked a Harvard researcher studying BRCA1/2 breast cancer what it would take to
even start to figure this out (as I had asked a City of Hope researcher whose poster on BRCA1/2 BREAST cancer at San Antonio prompted me to ask the question), and he declared that they needed to feel assured they would have large amounts of speciments/data and funding before they would even start being tempted to look at it (the City of Hope researcher was not interested at all and just brushed me off)

I have posted on the site asking for those with family histories of breast cancer to post whether any other family member's bc was her2+ but have not gotten overwhelming response.

I did graduate work in medical genetics over 32 years ago and haven't been involved in the field since so I am certainly not claiming any expertise...

My extensive reading just reinforces my understanding that what we don't know exceeds what we do and that generalizations which might influence
someones actions eg, whether or not they tell relatives about their breast cancer and give others a chance to be diagnosed early can be harmful

The internet can be full of lots of information--interpreting what is stated as "fact" can be difficult!

If the above is rather disjointed it is because I am suffering from 9 hours jetlag after transatlantic travel (sorry!)

[Joanne S]

Oh my gosh! I think I understood everthing in your post. No, not disjointed at all---you write very well. Your post in written in a manner I can understand. Now I see why you said over-simplified. Even knowing as much as I know, cancer is much more complex than I ever imagined. Thanks for taking the time to explain. Hope you had fun in your travel. Didn't see anything in your profile. Graduate work in genetics---how interesting. Are you a BC survivor or supporter? Like to know more about you.

Thanks again,

[Bev]

Would Foxp3 possibly explain no BC history on maternal side and unknown history on paternal side? BB

[Joanne S]

Per Lani's post : here is one
Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and
an important regulator of the HER-2/ErbB2 oncogene.

Bev, Your question:
Would Foxp3 possibly explain no BC history on maternal side and unknown history on paternal side? BB

Bev, Lani may be anwer your question.


I'm not sure if FOXP3 x-linked recessive gene or x-linked dominate. The following explain x-linked recessive and dominate:

X-linked inherited diseases occur far more frequently in males because they only have one X chromosome. Females must receive a copy of the gene from both parents to have such a recessive disease. However, they will still be carriers if they receive one copy of the gene.
Recessive (http://en.wikipedia.org/wiki/Recessive) genes on the X chromosome that cause serious diseases are usually passed from female carriers to their ill sons and carrier daughters. This is because males, who always have the disease and are not just carriers, would have to father a daughter to pass on the gene. This is unlikely because severe genetic diseases often cause death in childhood or early adulthood. Even those males who survive childhood are unlikely to father children because a sickly male will be less likely to find a mate (http://en.wikipedia.org/wiki/Mate). However, if the disease shows up late in life, or is not severe, he will pass the gene to all of his daughters. He can not pass it to his sons because a male receives his X chromosome from his mother.
A mother with one copy of the gene has a 50% chance of passing it to her children of both sexes, but her daughters will just be carriers of the gene unless their father has it too.


-X-LINKED RECESSIVE CARRIER MOTHER
http://upload.wikimedia.org/wikipedia/commons/a/a3/XlinkRecessive.jpg

--------



X-linked dominant is mode of inheritance (http://en.wikipedia.org/wiki/Mendelian_inheritance) in which a gene (http://en.wikipedia.org/wiki/Gene) on the X chromosome (http://en.wikipedia.org/wiki/X_chromosome) is dominant (http://en.wikipedia.org/wiki/Dominant)<SUP class=reference id=_ref-0>[1] (http://en.wikipedia.org/wiki/X-linked_dominant#_note-0)</SUP>. Females can be more frequently affected than males since they have two X chromosomes that could potentially carry the abnormal gene, whereas a male has only one. However, the Lyon hypothesis states that X-inactivation renders only one copy of the X chromosome active in each cell hence on average one would expect only one half of the cells to express the abnormal gene. The chance of passing on an X-linked dominant disorder differs between men and women.
This inheritance pattern is less common than X-linked recessive (http://en.wikipedia.org/wiki/X-linked_recessive).


X-LINKED DOMINANT - AFFECTED MOTHER

---A woman with an X-linked dominant disorder has a 50% chance of having an affected child.

http://upload.wikimedia.org/wikipedia/commons/f/fe/Xlink_dominant_mother.jpg



X-LINKED DOMINANT - AFFECTED FATHER

---The daughters of a man with an X-linked dominant disorder will all inherit the condition.

http://upload.wikimedia.org/wikipedia/commons/8/8c/X-link_dominant_father.jpg
<!-- / message -->

[Lani]

the story is not so simple with respect to others:


One of the first lessons taught in tumor genetics courses is that activation of a proto-oncogene requires mutation of a single allele, whereas inactivating a tumor suppressor gene requires biallelic inactivation. This difference was recapitulated in Knudson's two-hit theory to explain the genetics of retinoblastomas (Knudson, 1971) and helped identify the first tumor suppressor genes. Following this easy rule of thumb, the tumor suppressor protein p53 was originally classified as an oncogene, because introduction of a single mutant allele provides transforming activity. But once it was realized that p53 is a tumor suppressor that can acquire dominant-negative mutations, it became clear that tumor suppressor genes do not always require biallelic inactivation (Levine et al., 2004). In another variation on this theme, two new studies describe identification of the first X-linked tumor suppressor genes. One study describes involvement of the X-linked WTX gene in Wilms tumor (Rivera et al., 2007), and in this issue of Cell, Zuo et al. (2007) report that FoxP3 is an X-linked tumor suppressor gene involved in breast cancer.

What makes an X-linked tumor suppressor gene special? First, as males only carry one copy of the X chromosome, this allows for “one-hit” inactivation. Second, X chromosome inactivation results in transcriptional silencing of one of the two X chromosomes in female somatic cells to equalize the dosage imbalance of X-linked genes between males and females. Which of the two X chromosomes is inactivated is completely random, but once established, this pattern of inactivation is stably propagated to the daughter cells. As a result, females normally display a mosaic pattern of X inactivation: 50% of the cells inactivate the maternally inherited X chromosome, whereas the other 50% inactivate the paternal X chromosome. Consequently, X chromosome inactivation in combination with a single mutation in the active X chromosome can inactivate an X-linked tumor suppressor gene. Indeed, WTX is inactivated by monoallelic mutation targeting the active X chromosome in female patients (Rivera et al., 2007). Similarly, mammary tumors in FoxP3 mutant heterozygous mice have invariably inactivated the X chromosome carrying wild-type FoxP3. Thus, inactivation of X-linked tumor suppressor genes can be achieved by a “single-hit” event, both in males and in females.

Why have tumor suppressor genes on the X chromosome not been selected against during evolution? This may reflect a lack of sufficient selective pressure against these genes, especially considering that reproductive age generally precedes the onset of cancer. In fact, the risk that comes with an X-linked tumor suppressor gene is comparable to that associated with a haploinsufficient tumor suppressor gene, of which several examples exist (Santarosa and Ashworth, 2004). Nonetheless, the genetics of X-linked tumor suppressors might be more complex. First, X inactivation does not silence all genes on the X chromosome. Although there is clear evidence that FoxP3 is subject to X inactivation, silencing at the FoxP3 locus might be incomplete (Wildin and Freitas, 2005). Indeed, in 38% of the analyzed breast cancer tissue samples carrying somatic FoxP3 mutations, the wild-type FoxP3 allele is lost, suggesting leaky X inactivation at the FoxP3 locus. Secondly, in females carrying mutations in critical X-linked genes, selective X inactivation is observed due to negative selection of cells expressing the mutant allele. This selection, known as skewed X inactivation, allows for phenotypic suppression of X-linked dominant disorders in females by selecting for expression of the wild-type allele in relevant tissues (Figure 1). In fact, although inactivation of FoxP3 causes an autoimmune disorder (IPEX syndrome) in males, females with a single mutant FoxP3 allele are not affected by the disease, as skewing can select against expression of the mutant allele. Now, Zuo et al. (2007) show that FoxP3-heterozygous female mice develop breast cancer at an enhanced rate as they age. This leads to the peculiar notion that in female carriers of a mutant FoxP3 allele, skewed X inactivation selects against expression of the mutant allele in certain tissues to prevent autoimmune disease, whereas skewing selects for expression of the mutant allele during tumorigenesis in breast epithelial cells to promote breast cancer.


Mosaic expression of a mutant X-linked gene, such as FoxP3, in females depends on X chromosome inactivation. Growth of cells carrying a mutant allele can be actively suppressed by negative selection resulting in skewed X inactivation (right). Mechanism(s) for selection can be diverse, such as increased intrinsic cell death of cells carrying the mutant allele. However, clonal outgrowth of cells carrying a mutant allele can also occur, and this results in disease (left). Clonal outgrowth can be caused by secondary genetic changes (such as Ras activation), resulting in hyperproliferation of cells carrying a mutant allele or silencing of the wild-type allele through loss of heterozygosity or, in the case of FoxP3 and other X-linked tumor suppressor genes, through X chromosome inactivation.

How does FoxP3 act to suppress the development of breast cancer? FoxP3 belongs to the Forkhead family of transcription factors, of which several members (FoxO, FoxM, FoxG1) have been implicated in tumorigenesis. Initially, it was shown that FoxP3 is essential for the commitment of thymocytes to become regulatory CD4+ T cells (Tregs) with dedicated immunosuppressive functions (reviewed in Zheng and Rudensky, 2007). Indeed, FoxP3 is predominantly expressed in Tregs, where it can act as a transactivator and repressor of a large variety of genes. Zuo et al. present evidence for FoxP3 expression in breast epithilium and indicate that the HER-2/ErbB2 oncogene is a relevant target of FoxP3. Most tantalizing is their observation that ectopic expression of ErbB2 completely reverses the antitumorigenic effect of FoxP3, at least as measured in colony-formation assays in vitro. This outcome suggests that ErbB2 is the single most important target of FoxP3 in preventing tumorigenesis. Interestingly, Liu and colleagues previously proposed that ErbB2 is a pivotal target of FoxP3 in thymic epithelium where FoxP3 regulates differentiation of Tregs (Chang et al., 2005). This suggests that deregulated ErbB2 expression is responsible for both the autoimmunity in males and the increased tumor formation seen in females. However, a role for FoxP3 in thymic epithelium was recently disputed (Zheng and Rudensky, 2007), and ErbB2 was not identified as a major FoxP3 target by expression profiling in Tregs. Possibly, FoxP3 requires specific cofactors to repress ErbB2 expression, similar to the cooperation between NFAT and FoxP3 to repress IL-2 expression (Wu et al., 2006). In addition, several FoxP3-negative breast cancers express low levels of ErbB2, and FoxP3 can also suppress growth of ErbB2-negative breast cancer cell lines. Based on expression profiling of FoxP3-regulated genes in ErbB2-negative cells, the authors propose multiple other players in the ErbB2 signaling pathway. However, this seems to contradict the observation that ErbB2 expression alone can overcome the tumor-suppressive effect of FoxP3. Clearly, the situation downstream of FoxP3 is more complex than mere regulation of ErbB2 signaling.

Although the data at hand indicate that FoxP3 acts in breast epithelium to suppress breast cancer, it remains possible that Treg function also contributes. Mosaic FoxP3 expression in Tregs may result in partial impaired Treg function without disease and elevated expression of inflammatory cytokines. Given that inflammation is increasingly recognized as a contributing factor in tumorigenesis (reviewed in Karin and Greten, 2005), increased and sustained inflammation may provide a mechanism for a more general involvement of FoxP3 in cancer development. Clearly, X-linked tumor suppressor genes are the new kids on the block, and it will be of interest to find out why and how nature tolerates these genetic booby traps.

^^^

So its not just simple dominant or recessive--it is which X is inactivated in any one cell and whether the other X is mutated ...and that is not the whole story!

[Joanne S]

Thanks Lani, I merely gave the definition and simplified examples for x-linked genes. I know it is not as simple as dominant or recessive, but I do understand that Foxp3 is x-linked (female). I in no way attempted to answer Bev's question.

I read it all, but the majority of your post was Way way over my head (usual for me), but I do understand there is no definite answer to Bev's question yet.


Would Foxp3 possibly explain no BC history on maternal side and unknown history on paternal side? BB
<!-- / message -->Bev,
In a nut shell (per Lani):
"So its not just simple dominant or recessive--it is which X is inactivated in any one cell and whether the other X is mutated ...and that is not the whole story!"

Bev, In my words, too many combinations and too many unknowns to answer your question---sounds like the possibility exists that is could be both maternal and paternal or some mutations of FOXp3.

I don't know why this particular article was originally posted, but when Lani posts the findings of recent trials or studies, it prompts me to get an idea of the complexity of BC and to learn some of the definitions of the terms used to describe the study's objective, including the setting, criteria, conditions, interpretation, possibilities, findings, results and/or non-conclusive finding---none the less all beneficial in some way for future studies, treatment or cures. Perhaps other Her2 members/readers of Lani's posts are as intelligent as Lani is or are much more knowledgable in this arena than I am. I just try to share the basics that I learned with others who are interested and whose knowledge base is as small as mine.

There I go rambling again. I've always been a type of night owl, but now I have my days and nights mixed up. I've been awake all night and morning ---I'll probably pass out at noon and wake up at midnight. Aye Aye aye.

<!-- / message -->

[Bev]

Thanks J & L. When I first read the post I thought perhaps the paternal link could explain why me. As usual, it looks like things are more complex. That's OK. I just want to understand. Bev

[Lani]

researchers busy. Thankfully, they have figured out that her2+ breast cancers are distinctive (and perhaps there are several/many subgroups of her2+ breast cancer), allowing them to detect a benefit in using herceptin in some patients (had it not been for being able to detect/predict a group of patients in whom it had an effect, they would have given up development of herceptin years ago). A couple of years ago I listed the breast cancer cell lines which are her2+--it helps to keep a list on hand when reading articles as it makes it more likely the article pertains to her2+ breast cancer ie, if an article claims efficacy of curcumin, green tea extract, etc. Otherwise its like saying treatment x helps skin or stomach cancer ie, its likely a whole other ballgame.

I have NO DOUBT of the intelligence of her2 members... what I doubt is their CONFIDENCE in their own ability to understand articles. Yes, they are written in "medicalese" but a medical dictionary and some help from Google as well as using the "search" function as I try to post news items in "nonMedicalese" English as well as abstracts go a long way.

Since many of the answers are truly unknown, your "take" on things is no less valid than that of others.

Knowledge is power...even when it is only the knowledge that we still don't understand an issue.