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Mutation leading to biological changes may play role in cancer

A GCRC researchteamgenerates the first mouse expressingEstrogen Receptormutation early on in development

A new study from theGoodman Cancer Research Centre (GCRC)has revealed significant biological changes in mice expressing an activated, mutant form oftheEstrogenReceptor alpha(ER alpha),sheddingnew light on the role of this important gene in development and cancer.Over-expressed in approximately70 % of breast cancer cases, the Estrogen Receptor is often associated with breast cancer therapy resistance when it mutates and therefore cancontribute topoor patient outcomes.To understand how the biological effects ofER alpha mutations can lead to cancer, researchers at the GCRC havegeneratedthe first mouse model expressing one of these mutations early in development,bringingnewinsightonits effectson the development ofthesexual organs.

The research, led by Dr. William Muller at the GCRC andpublishedinGenes and Development,reveals dramatic developmental defects in the reproductive organs, mammary glands and bones of the miceexpressing mutations in the Estrogen Receptor. Not only didthemutation causestuntedgrowth andabnormal sexual development in both female and male mice, it alsotriggeredphysical andgeneticchanges in male mice that caused them to phenotypicallyresemble female mice.

“The observed feminization of the male mice is consistent with the long-standing notion that estrogen signaling is essential in the sexual differentiation of reproductive tracts in both sexes, " notesProf. Muller. "Understandingthe biological effects of this mutation in the context of the breast will hopefully allow us to develop better therapeutic approaches for cancer patients in the future."

Thesenewfindingsfrom the GCRC support the existing science which reveals changes in criticaldevelopmentaland behavioural changes inmalemice withgenetic modification ofER alpha. Pathologically, male mice display a dramatic atrophy of the testesand seminalvesiclesas well as an absence of the preputialglands,both of which are inherentin sexual and dominancebehaviourin mice,(Bronson andCaroom1971; Bronson and Marsden 1973).

Developmental biology shedding light on cancer?

The changes in development seen in these mice could very well relate tospecific aspects ofcancer.Interestingly,ESR1(thehumangenethatcorresponds toER alpha)was found to be mutated in some endometrial cancers and hyper-estrogenismcan occur congenitally in men and is linked with prostate cancer as well as other types of pathology.Indeed,developmental biology is important in the study of cancer and understanding how genes affect development of certain organs can tell us a lot about how those same genes can cause or contribute to cancer.

“Our observations provide critical insights into the role oftheEstrogenReceptorduring development,”says Alexandra Simond, a 鶹AV graduate student and first author of the published work.“Our findingsweredefinitelyunexpected,but webelievetheywillhelp strengthenour understanding of the role of ER alpha indevelopment and cancer,whichultimatelywill lead tobetter personalized treatmentto those that need it."

Prof. Muller acknowledges the support that he has received fromfunding agenciesincludingtheCanadian Institutes of Health Researchandthe Canada Research Chairs Program,and theinnovation of thecore technology platforms at the GCRCwithout whichthis research would not have been possible.

Not onlydoesthis studyfromthe GCRCprovideadeeperunderstanding of thekeyfunctionalityof the Estrogen Receptor during development,it also shedsnew light onthe evolving phenotype ofcertainmicewhichis very striking.Further research will be required to more definitively link the observed phenotypes with specific aspects of breast and potentially other cancers where it is mutated.

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Link to the study published in Genes and Development:

DOI:10.1101/gad.339424.120

Media contact details:

Goodman Cancer Research Centre, 鶹AV:

MarieMoucarry, Communications Advisor, 438-993-6127,marie.moucarry2 [at] mcgill.ca

Faculty of Medicine, 鶹AV:

Jason Clement, Communications Manager,514-865-6990,jason.clement [at] mcgill.ca

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