progress in discovering how some ER+her2+ bc starts, what best treatment may be

[Lani]

Looks like 17 AAG or drugs related to it (heat shock protein 90 inhibitors) might be a good drug for/preventative for those Er+her2+ bcs with high cyclin D1 causing high chromosomal instability

Drugs targeting chromosomal instability may fight a particular breast cancer subtype
[Eureka News Service]

PHILADELPHIA — Another layer in breast cancer genetics has been peeled back.

A team of researchers at Jefferson's Kimmel Cancer Center (KCC) led by Richard G. Pestell, M.D., PhD., FACP, Director of the KCC and Chair of the Department of Cancer Biology, have shown in a study published online Feb. 6 in the Journal of Clinical Investigation that the oncogene cyclin D1 may promote a genetic breakdown known as chromosomal instability (CIN). CIN is a known, yet poorly understood culprit in tumor progression.

The researchers used various in vitro and in vivo model systems to show that elevated levels of cyclin D1 promotes CIN and correlate with CIN in the luminal B breast cancer subtype. Cyclin D1 protein is elevated in breast, prostate, lung and gastrointestinal malignancies.

The findings suggest that shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype. Luminal B breast cancer has high proliferation rates and is considered a high grade malignancy.

Estrogen or progesterone receptor positive and HER2 positive cancers indicate luminal B, and about 10 percent of patients are diagnosed with it every year, though many do not respond well to treatment. The identification of CIN in luminal B provides a new therapeutic opportunity for these patients.

"Cyclin D1 has a well defined role in cell proliferation through promoting DNA replication," says Dr. Pestell. "My team was the first to discover that cyclin D1 also has alternate functions, which include regulating gene transcription at the level of DNA. We were interested in discovering the function of DNA associated cyclin D1."

To help answer this, the researchers, including lead author Mathew C. Casimiro, Ph.D., of the Department of Cancer Biology at Thomas Jefferson University, first needed to directly access cyclin D1's role in gene regulation.

They applied an analysis known as ChIP sequencing to study the protein's interactions with genes that comprise the entire mouse genome, and found it occupied the regulatory region of genes governing chromosomal stability with high incidence.

They went on to show cyclin D1 promoted aneuploidy and chromosomal rearrangements typically found in cancers.

Faulty chromosomes—either too many or too few, or even ones that are the wrong shape or size—have been shown to be the crux of many cancers. However, a major question of cancer genetics is the mechanisms of CIN. What causes the breakdown in chromosomal stability?

As cyclin D1 expression is increased in the early phases of tumorigenesis, cyclin D1 may be an important inducer of CIN in tumors.

To analyze the association between CIN and cyclin D1 expression in the context of breast cancer, the team aligned an expression of a 70-gene set with the highest CIN score against over 2,000 breast cancer samples. They stratified the samples based on previously described subtypes and aligned them with cyclin D1 expression profiled across the dataset.

A significant correlation among CIN, cyclin D1 and the luminal B subtype was identified, and it was apparent that the relationship between these levels was subtype specific.

"Interestingly, previous studies have presented contradictory results," Dr. Pestell says. "Many studies have suggested a positive correlation between cyclin D1 expression and outcomes, while others have shown reduced survival. Here, we've dug deep, using a genome-wide analysis, and found that overexpression of the protein appears to be directly associated with the genes involved in CIN and this correlates with the luminal B subtype."

Drugs targeting chromosomal instability for cancer therapy have been explored, but a sub-stratification rationale for the luminal B subtype has not been established. The research presented in this study suggests such a target is worthy of further investigation.

"There is a big drive towards using targeting therapies for stratified breast cancers," says Dr. Casimiro. "What we are thinking is that there are a growing number of drugs that target aneuploidy, like AICAR and 17-AAG, that may be used as an adjuvant therapy in patients with luminal B breast cancer."

OPEN ACCESS: ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice
[Journal of Clinical Investigation; ]

Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1-/- mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1-rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland-targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.

[michka]

Another interesting article. Thanks Lani!

"shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype". Do any exist? Michka

[Lani]

the article quotes " drugs that target aneuploidy, like AICAR and 17-AAG" as being likely candidates to prevent chromosomal instability (which causes aneuploidy)

[Rich66]

...data suggest that cyclin D1 contributes to CIN and tumorigenesis

Mol Cancer Ther. 2012 Jan 18. [Epub ahead of print]
The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo.

Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, Nomura K, Mimura S, Kobayashi M, Aritomo Y, Kobara H, Mori H, Himoto T, Okano K, Suzuki Y, Murao K, Masaki T.
Source

1Gastroenterology and Neurology, Kagawa University Schhol of Medicine.

Abstract

Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with metformin's anti-tumor effect. We used MKN1, MKN45 and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45 and MKN74 in vitro. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially in cyclin D1, cyclin-dependent kinase4 (Cdk4), Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of EGFR and IGF-1R in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo.

PMID:22222629 [PubMed - as supplied by publisher]

[Becky]

I am also thinking out loud about the role of vitamin D in the prevention of such cancer since one of its roles is to stabilize DNA as well as its assist in cell apoptosis.

Hmmm

[caya]

Becky, I get so upset (pissed off, actually!) about the discovery of the role Vitamin D can play in the prevention of breast cancer.
I think of the years when I stayed out of the sun, as we were told too much sun would give us skin cancer. Especially up here in Canada, where the sun's rays are less strong.
So now I'm taking 4500 U of Vitamin D3/day.

all the best
caya

[schoolteacher]

Thanks for the information.

Amelia