Low levels of tumour-suppressing gene identified as reason behind endometrial cancer

Endometrial cancer, also called uterine cancer, is the fourth most common malignancy in women. Unfortunately, the cause of this dreadful disease is largely unknown. But for the first time, a study, which was done scients at the ICMR-National institute for Research in Reproductive and Child Health (NIRRCH), has found the missing key—a gene called HOXA10.
What does this gene called HOXA10 do?
HOXA10 acts like a tumour suppressor (a brake) in the uterus and when that fails, it sets the system in a continuous proliferation mode, causing cancer with time.
The uterus is where a foetus grows and develops when a woman is pregnant. Endometrial cancer starts in the endometrium which is the inner lining of the uterus. It is estimated that more than 12,000 women in India alone suffered from endometrial cancer in 2020, of which 50 per cent succumbed to it.

Why incidence of endometrial cancer is high? 
“The incidence rate of endometrial cancer is increasing rapidly and is predicted to increase more than 50 per cent in the next two decades. Unfortunately, the cause of this dreadful cancer is largely unknown,” said Dr Deepak Modi, lead investigator of the study, “Loss of HOXA10 causes endometrial hyperplasia progressing to endometrial cancer.” It was published in the Journal of Molecular Endocrinology.

Endometrial hyperplasia is an abnormal growth of the endometrial cells and young women can develop endometrial cancer as they age. Till date the cause of development of endometrial hyperplasia and why the hyperplasia progresses to endometrial cancer with age is also unknown.
Study can guide new therapies
The study done scients at NIRRCH has identified HOXA10 as the trigger. More studies are being conducted upon genetically modified mice that had very low levels of HOXA10. These mice were developed with the help of Dr Nirmalya Ganguli and Dr Subeer Majumdar at the National institute of Animal Biotechnology (NIAB) in Hyderabad.

The uteri of these animals looked very unusual. “They had lots and lots of epithelial cells of the glands growing abnormally in the uteri of young animals. Some old animals (more than one year, lifespan of mice is 1.5 to 2 years) had all the signs of endometrial cancer. This was then systematically studied the researchers and they found that upon losing HOXA10, almost 80 per cent of young animals had endometrial hyperplasia and when they became old, all developed cancer. This did not happen when the animals had normal levels of HOXA10,” said Dr Modi who is head of Molecular and Cellular Biology Laboratory, NIRRCH.
The researchers also figured out the mechanism which this happens. They showed that young mice with low HOXA10 had excessive levels of other cancer-causing genes like Wnt4, beta catenin, Sox9 and Yap1, which allowed the cells to grow very rapidly causing cancer. This is unprecedented as this is the first study that has conclusively shown that just losing one gene (HOXA10) can cause endometrial cancer.
Interestingly, many women with endometrial cancer, who have low levels of HOXA10, also have excessive amounts of cancer-causing genes like Wnt4 and beta catenin. “Therefore, we think HOXA10 acts like a tumour suppressor (a brake) in the uterus and when it fails, it sets the system in a continuous proliferation mode causing cancer with time,” added Dr Modi.
This discovery has very important implications. First it provides an explanation of how endometrial hyperplasia is caused and why it can progress to endometrial cancer. Modi said that this new finding should be used for new therapies. “Also, now pathologs can use levels of HOXA10 and other pro-tumour genes as a possible predictive marker to determine if endometrial hyperplasia can progress to cancer. Drug companies can use this animal model to identify and test new drugs to find cure cancers,” he added.