Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses

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.

Automated summary

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.