Epigenetic Reprogramming of HOXC10 in Breast Cancer

Aromatase inhibitors (AI) are use in the treatment of estrogen receptor (ER) positive breast cancer, but tumors often develop resistance to these. In the latest edition of Science Translational Medicine Thushangi Pathiraja and colleagues identified ways in which cancer cells develop this resistance by ’epigenic reprogramming’  – using the mechanisms for ‘switching off ‘ genes seen in normal cells as they differentiate and take on specialist functions.  The NIH-funded study found methylation of DNA (in a ‘CpG shore’ which overlapped with a ER binding site) resulting in reduced expression of the HOXC10 gene in breast cancer cell lines. Even when ER signaling was blocked in cell lines and tumors this only resulted in short-term HOXC10 expression and the cells went on to increas DNA methylation and silencing of HOXC10.

The study linked reduced HOXC10 with decreased apoptosis and caused antiestrogen resistance. An analysis of paired primary and metastatic breast cancer specimens showed HOXC10 was reduced in tumors that recurred during AI treatment.

Drawing on this study and previous work the authors propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival. AI treatments induce these genes to cause short-term apoptosis and clinical benefit, but long-term AI treatment results in permanent repression of these genes via methylation resulting in resistance.  Therefore the authors propose future investigation of therapies aimed at inhibiting AI-induced histone and DNA methylation in order to block or slow down AI resistance.

Related Links:

Pathiraja TN, Nayak SR, Xi Y, et al. Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer Sci. Transl. Med. 6, 229ra41 (2014).

HOXC10 in CancerGenetics Web

Mitochondrial DNA – role in cancer?

Mitochondria (plural of mitochondrion) are membrane-bound organelles (the cell’s ‘mini organs’) found in nearly all cells which play a vital role as “cellular power plants” by generating adenosine triphosphate (ATP), used by cells as a source of chemical energy. Mitochondria also play a role in cellular signaling, cellular differentiation, cell death, control of the cell cycle and cell growth, and other roles. Mitochondria are unusual in that they contain their own DNA, whilst the rest of the human genome is concentrated in the nucleus of the cell. Also, Mitochondrial DNA (mtDNA) is only inherited from mothers, whist the DNA in the cells nucleus is inherited from both mother and father.

Diagram of the structure of a mitochondrion from Wikimedia Commons under a Creative Commons CC0 license.

mtDNA has been linked carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. mtDNA lacks introns, so mutations tend to occur in coding sequences and it is thought that accumulation of these mutations may lead to tumor formation (Radpour et al, 2009). Research into of role of mtDNA mutations in cancer is advancing understanding of their functional role in carcinogenesis, value in diagnosis and monitoring, and potential therapeutic implications….

 

See more at:

http://www.cancerindex.org/geneweb/gmtdna.htm

New insight into Prostate Cancer susceptibility

New research published in Nature Genetics (February 2014) by Qilai Huang and colleagues gives a new insight into the mechanisms by which men with a specific polymorphism (variation in a gene) have increased susceptibility to Prostate Cancer.

The team involving researchers in Finland, Sweden and China found that the ‘rs339331’ polymorphism is located  within a functional binding site of the HOXB13 gene and  causes an up regulation of RFX6, a protein which is associated with  prostate cancer cell proliferation, migration and invasion. Also, their analysis  of prostate tumours found a significant association between the T allele at rs339331 and higher levels of RFX6 mRNA.

For more details please see:

The CancerIndex page on the HOXB13 gene:

http://www.cancerindex.org/geneweb/HOXB13.htm

Nature Genetics:

Huang Q et al. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics 46, 126–135 (2014)

CUX1 gene mutations linked to tumour growth

A new study from the Sanger Institute (Wong CC et al. Nature Genetivs, 2013) found that CUX1 is mutated at a relatively low frequency, but across many different types of cancer.

CancerIndex has added a page: http://www.cancerindex.org/geneweb/CUX1.htm

The study used genetic data from over 7,600 cancer patients, collected and sequenced by the International Cancer Genome Constortium (ICGC) and other groups. Theyfound that when CUX1 is deactivated, it had a knock-on effect on a biological inhibitor, PIK3IP1, reducing its inhibitory effects. This mobilises an enzyme responsible for cell growth, phosphoinositide 3-kinase (PI3K), increasing the rate of tumour progression.

See more at: http://www.cancerindex.org/geneweb/CUX1.htm

Cancer Treatments and Hair Loss

Hair loss (alopecia) is a common and usually temporary, but often very distressing, side effect of chemotherapy.

CancerIndex has split out information on chemotherapy related alopecia onto a dedicated page: http://www.cancerindex.org/Alopecia.htm

As well as links to guides on this topic the page also includes an NHS Choices video in which Jessica, a breast cancer patient, describes how the hair loss affected her. The video also includes expert advice from HeadStrong Coordinator Tansy Bateman.

The page also pulls in research abstracts from PubMed. Boughton et al.  interviewd Australian women who described alopecia as the most distressing corporeal feature of the ovarian cancer experience. In an earlier study Hilton et al. asked the question “Have men been overlooked?” and found that both women and men had negative (and often similar) feelings about hair loss. There are a few published studies on scalp cooling to reduce hair loss during chemotherapy, with mixed success. van den Hurk et al report on results of the Dutch Scalp Cooling Registry, involving 1411 chemotherapy patients.

http://www.cancerindex.org/Alopecia.htm

Cancer Centers – Update

Our list of Cancer Centres has been updated:
http://www.cancerindex.org/clinks8.htm

It has grown to a list of over 260 centers, so rather than the very long static list that it used to be, it is now displayed in a ‘data table’ that you can search, filter and order.

Does this work for you? I’d love to hear your feedback.

It is amongst the top 20 most visited pages on the site. It is not a definitive list of all cancer centers but rather it focuses on large non-profit centers around the world including “Comprehensive Cancer Centres” (or similar) .

Of course there are many other hospitals not listed here; many local hospitals work closely with the larger specialist centres – this varies depending on your location and healthcare system.