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New study rewrites the role of estrogen in cervical cancer.

Scientists have prior evidence that the hormone estrogen is a major driver in the growth of cervical cancer, however, a new study from the University of Wisconsin-Madison examining genetic profiles of 128 clinical cases reached a surprising conclusion, estrogen receptors all but vanish in cervical cancer tumours.  The team state that this finding further bolsters the understanding of cervical cancer’s progression and offers valuable new targets to fight the disease.  The opensource study is published in the journal Proceedings of the National Academy of Sciences.

The current study used gene expression profiling on 128 specimens from the Study to Understand Cervical Cancer Early Endpoints and Determinants, or SUCCEED. More than 4,000 women are participating in the SUCCEED study, a major effort to understand the second-leading cause of cancer in women globally. It is led by the National Cancer Institute (NCI) and the University of Oklahoma Health Sciences Center.

Cervical cancer, which used to be the leading cause of cancer deaths for women in the United States, is a medical success story in developed nations state researchers. Thanks to widespread early screening via Pap tests and the availability of an HPV vaccine, rates in the U.S. are down to about 12,000 cases and 4,000 deaths annually.  However, it remains a major threat globally, with more than 500,000 new cases per year, about half of which will be fatal. It’s the third leading cause of cancer deaths for women worldwide. Early detection and treatment of lesions caused by HPV can all but eliminate the onset of cervical cancer, however, many countries do not have access to early screening tests. Further, the HPV vaccines are among the most expensive vaccines available and their implementation is far from complete.

Previous studies show that virtually all cervical cancers derive from human papillomavirus (HPV) infection. The specimens in the current study came from four distinct groups, healthy patients, patients with either early or advanced complications due to HPV infection, and those with cervical cancer.  The patients allowed researchers to study the full progression of viral infection to cancer, a unique opportunity among human cancers.

Earlier studies have shown that a hallmark of HPV-associated disease is a dramatic increase in levels of a protein called p16, which normally is involved in regulating cell division. In profiling gene expression in the 128 specimens, the team realised that they needed to find out what other genes might be behaving like p16. This is where they encountered the surprise estrogen receptor expression doing the complete opposite of p16.  The data findings showed that estrogen receptors are in the healthy cells. However, as the cells became cancerous, the levels of estrogen receptor alpha crash to the point of being undetectable.

The team at first assumed there was a flaw in the study.  They explain that P16 and estrogen were as polar opposite as one can get. When looking at similarities between the 54,000 measurements on the human genome, p16 would be number one and estrogen would be 54,000.  The lab go on to add that other measurements for hundreds of other genes that respond to estrogen made it clear that levels of the estrogen receptor and of the genes it controls are a powerful marker for cervical cancer progression.

The group conducted microscopic analysis of the samples for further insights. Here, they observed that while estrogen receptor was absent in cancer cells, it was prevalent and in many cases increased in the so-called tumour microenvironment, the area around the tumour that helps it grow.  The data finding highlights that something critical is happening between the microenvironment and the tumour itself, allowing the tumour to thrive in spite of its inability to ‘see’ estrogen.  Thus the team hypothesize to understand the role of estrogen, they now have to look at how the tumour and the microenvironment communicate with one another,’ den Boon says.

The researchers now plan to grow populations of cells in a very miniaturized state in ways that they can reach out and talk to each other through tiny channels, and stay distinct.  The team state that the project will attempt to intercept the biochemical signals that are going back and forth between the microenvironment and the tumour. Small molecule therapeutics could be developed to interfere with the signals and suppress tumour growth.

The team surmise that the current study offers another avenue to target and alter the disease progression. Since estrogen also plays an important role in other cancers, including breast cancer and prostate cancer, they go on to add that this work has the potential to benefit other cancer-fighting efforts.

Source:  University of Wisconsin-Madison


Negative correlation between ERα and p16 expression during cervical cancer progression.  IHC stains for ERα (Top) and p16 (Bottom) in a cervical specimen representing complete disease progression.  Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling.  Ahlquista et al 2015.
Negative correlation between ERα and p16 expression during cervical cancer progression. IHC stains for ERα (Top) and p16 (Bottom) in a cervical specimen representing complete disease progression. Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Ahlquista et al 2015.

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