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

Aging Cell. 2022 Oct;21(10):e13665. doi: 10.1111/acel.13665. Epub 2022 Sep 15.


A major limitation in the use of mouse models in breast cancer research is that most mice develop estrogen receptor-alpha (ERα)-negative mammary tumors, while in humans, the majority of breast cancers are ERα-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 ERα-negative, while they are ERα-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 ERα axis of the mitochondrial UPR and the ERα-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 ERα-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 ERα.

Keywords: ER stress; XBP-1; aged mammary gland; aging; endoplasmic reticulum; estrogen receptor-alpha; mitochondrial UPR; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Carcinogenesis / genetics
  • Estrogen Receptor alpha* / genetics
  • Estrogen Receptor alpha* / metabolism
  • Female
  • Humans
  • Mice
  • Oncogenes
  • Receptors, Estrogen* / metabolism
  • Unfolded Protein Response / genetics


  • Estrogen Receptor alpha
  • Receptors, Estrogen