Journal
AGING CELL
Volume 21, Issue 10, Pages -Publisher
WILEY
DOI: 10.1111/acel.13665
Keywords
aged mammary gland; aging; endoplasmic reticulum; ER stress; estrogen receptor-alpha; mitochondrial UPR; unfolded protein response; XBP-1
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Funding
- NIH [U01CA237091, R01AG059635-01]
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A major limitation in breast cancer research using mouse models is that most mice develop estrogen receptor-alpha (ER alpha)-negative mammary tumors, while in humans, the majority of breast cancers are ER alpha-positive. However, a new study using an inducible mouse model revealed that mammary tumors in young mice are ER alpha-negative, while they are ER alpha-positive in aged mice. The study also identified genes involved in the activation of ER alpha axis and the regulation of UPR stress responses in aged female-derived mammary tumors. These findings suggest that aging alters the oncogenic trajectory towards ER alpha-positive breast cancer subtype.
A major limitation in the use of mouse models in breast cancer research is that most mice develop estrogen receptor-alpha (ER alpha)-negative mammary tumors, while in humans, the majority of breast cancers are ER alpha-positive. Therefore, developing mouse models that best mimic the disease in humans is of fundamental need. Here, using an inducible MMTV-rtTA/TetO-NeuNT mouse model, we show that despite being driven by the same oncogene, mammary tumors in young mice are ER alpha-negative, while they are ER alpha-positive in aged mice. To further elucidate the mechanisms for this observation, we performed RNAseq analysis and identified genes that are uniquely expressed in aged female-derived mammary tumors. We found these genes to be involved in the activation of the ER alpha axis of the mitochondrial UPR and the ER alpha-mediated regulation of XBP-1s, a gene involved in the endoplasmic reticulum UPR. Collectively, our results indicate that aging alters the oncogenic trajectory towards the ER alpha-positive subtype of breast cancers, and that mammary tumors in aged mice are characterized by the upregulation of multiple UPR stress responses regulated by the ER alpha.
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