What is DNA methylation and what is the matter with colon cancer/breast cancer and oestrogen?
There are a number of studies that are trying to understand the correlation between hormonal replacement therapy and DNA methylation which could trigger cancer. Two different types of correlation have been studied, the one linked to colon cancer and another one linked to breast cancer. The reasoning behind it, is that HRT could influence DNA methylation and therefore those changes could lead to the appearance of cancer.
So, DNA methylation is such an interesting thing and perhaps a novelty or a new word to many of you. DNA methylation is an epigenetic change which means literally that some changes ‘are related to’ or ‘arise from’ non-genetic influences. A every common example of this is the environment and pollution and how it can affect the information contained in our genes. This mechanism usually occurs by ‘tagging’ or adding of one or many small molecules called ‘Methyl’ in our DNA. This usually modifies the way these genes will be read and function.
It means that a gene can be ‘muted’ or silenced and therefore can’t express itself (like when you ‘mute’ a radio during the newscast you can’t hear the information), or maybe its expression can differ from what a normal situation would be.
The most widely understood DNA methylation is the addition of one molecule of methyl, at what it is informally known as the “fifth base” of DNA (a specific position within the DNA chain). These methyl molecules project into the major groove of DNA and inhibit their transcription, therefore in this specific case, the information contained in this gene is no longer expressed. Alterations in the pattern of DNA methylation have been recognised as an important step of cancer development. Less methylation has also been implicated in the development and progression of cancer through different mechanisms. Typically in a normal scenario(healthy), there is (1) a fair amount of methylation in genes responsible for suppressing the appearance of tumours (known as tumour suppressor genes) and (2) really low levels of methylation in genes that promote cancer growth and development (known as oncogenes).
So the hypothesis is that use of oestrogen or progesterone (or both), could be associated with the methylation of genes that are sensitive in the colon or in breast tissue, to receive the signals from hormones such as oestrogen or progesterone.
A significant alteration to the DNA methylation pattern in genes in these tissues could lead potentially to cancer. It has to be pointed out that the risk associated with cancer, is strongly dependent on (1) duration, (2) dosage, (3) type of hormones and (4) combination of hormones. We have extensively talked about HRT concerns in previous articles, and the possible side effects arising with HRT. What is the common consensus now is that single oestrogen therapy, or short-term combined HRT use (initiated usually around the time of menopause or shortly before) does not appear to increase breast cancer risk. However on the other end, long-term combined use of HRT starting in the menopause, is linked to breast cancer, with an increased risk the longer you use this therapy.
Studies have been done, comparing women that never used HRT with women that were using it and the results show…
…that, despite the small sample set, a number of genes was identified whose methylation state is specifically associated with the use of HRT. This has plausible links to breast cancer or colon cancer development. Replication of these results by independent teams and in larger numbers are yet much needed, as well as testing the hypothesis that methylation of these genes is altered in HRT-associated breast and colon tumours. However, an initial correlation is clear. The big issue with HRT today, is that they are not considered very safe amongst public opinion but there isn’t sustainable amount of information about it. So from these recent publications, it appears to be clear that progesterone and oestrogen are responsible for modifications in the DNA methylation pattern. This phenomenon is one of the causes or one of the factors that influence cancer. So if you are wondering whether to take HRT or not, or if you are aware of a strong history of cancer in your family, it is strongly advisable to consider the risks and benefits with your menopause expert or GP, as only them can guide you through the best therapies available for you.
By Ornella Cappellari
Carcinogenesisvol.31 no.6 pp.1060–1067, 2010doi:10.1093/carcin/bgq009Advance Access publication January 11, 2010
Hormone therapy, DNA methylation and colon cancer
Anna H.Wu, Kimberly D.Siegmund, Tiffany I.Long,Wendy Cozen, Peggy Wan, Chiu-Chen Tseng, Darryl Shibata and Peter W.Laird
Epigenetics. 2019 Feb;14(2):146-157. doi: 10.1080/15592294.2019.1580111. Epub
2019 Mar 1.
Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide
data from the normal breast study.
Harlid S, Xu Z, Kirk E, Wilson LE, Troester MA, Taylor JA.
European Journal of Cancer (2013) 49, 52– 59 Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial Mia Fahle´, Tommy Fornander, Hemming Johansson, Ulla Johansson, Lars-Erik Rutqvist, Nils Wilking, Eva von Schoultz.
Endocrine. 2004 Aug;24(3):255-7.Hormone replacement in women with breast cancer: the HABITS study. Brincat M1, Muscat Baron Y, Ciantar E.