A GCRC research听team听generates the first mouse expressing听Estrogen Receptor听mutation early on in development听
A new study from the听Goodman Cancer Research Centre (GCRC)听has revealed significant biological changes in mice expressing an activated, mutant form of听the听Estrogen听Receptor alpha听(ER alpha),听shedding听new light on the role of this important gene in development and cancer.听Over-expressed in approximately听70 % of breast cancer cases, the Estrogen Receptor is often associated with breast cancer therapy resistance when it mutates and therefore can听contribute to听poor patient outcomes.听To understand how the biological effects of听ER alpha mutations can lead to cancer, researchers at the GCRC have听generated听the first mouse model expressing one of these mutations early in development,听bringing听new听insight听on听its effects听on the development of听the听sexual organs.听听听
The research, led by Dr. William Muller at the GCRC and听published听in听Genes and Development,听reveals dramatic developmental defects in the reproductive organs, mammary glands and bones of the mice听expressing mutations in the Estrogen Receptor. Not only did听the听mutation cause听stunted听growth and听abnormal sexual development in both female and male mice, it also听triggered听physical and听genetic听changes in male mice that caused them to phenotypically听resemble female mice.听听
鈥淭he 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, " notes听Prof. Muller. "Understanding听the 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."听
These听new听findings听from the GCRC support the existing science which reveals changes in critical听developmental听and behavioural changes in听male听mice with听genetic modification of听ER alpha. Pathologically, male mice display a dramatic atrophy of the testes听and seminal听vesicles听as well as an absence of the preputial听glands,听both of which are inherent听in sexual and dominance听behaviour听in mice,听(Bronson and听Caroom听1971; Bronson and Marsden 1973).听
Developmental biology shedding light on cancer?
The changes in development seen in these mice could very well relate to听specific aspects of听cancer.听Interestingly,听ESR1听(the听human听gene听that听corresponds to听ER alpha)听was found to be mutated in some endometrial cancers and hyper-estrogenism听can occur congenitally in men and is linked with prostate cancer as well as other types of pathology.听Indeed,听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.听
鈥淥ur observations provide critical insights into the role of听the听Estrogen听Receptor听during development,鈥澨齭ays Alexandra Simond, a 黑料不打烊 University graduate student and first author of the published work.听鈥淥ur findings听were听definitely听unexpected,听but we听believe听they听will听help strengthen听our understanding of the role of ER alpha in听development and cancer,听which听ultimately听will lead to听better personalized treatment听to those that need it."听
Prof. Muller acknowledges the support that he has received from听funding agencies听including听the听Canadian Institutes of Health Research听and听the Canada Research Chairs Program,听and the听innovation of the听core technology platforms at the GCRC听without which听this research would not have been possible.听听
Not only听does听this study听from听the GCRC听provide听a听deeper听understanding of the听key听functionality听of the Estrogen Receptor during development,听it also sheds听new light on听the evolving phenotype of听certain听mice听which听is very striking.听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.听听
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Link to the study published in Genes and Development:听
DOI:听10.1101/gad.339424.120
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Media contact details:听
Goodman Cancer Research Centre, 黑料不打烊 University:听听
Marie听Moucarry, Communications Advisor, 438-993-6127,听marie.moucarry2 [at] mcgill.ca听
听
Faculty of Medicine, 黑料不打烊 University:听
Jason Clement, Communications Manager,听514-865-6990,听jason.clement [at] mcgill.ca听