Tag Archives: Research Commentary

Epigenetic Reprogramming of HOXC10 in Breast Cancer

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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

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New insight into Prostate Cancer susceptibility

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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

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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