TY - JOUR
T1 - Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses
AU - Jenkins, Edmund Charles
AU - Chattopadhyay, Mrittika
AU - Gomez, Maria
AU - Torre, Denis
AU - Ma'ayan, Avi
AU - Torres-Martin, Miguel
AU - Sia, Daniela
AU - Germain, Doris
N1 - Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - ER stress
KW - XBP-1
KW - aged mammary gland
KW - aging
KW - endoplasmic reticulum
KW - estrogen receptor-alpha
KW - mitochondrial UPR
KW - unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85137979396&partnerID=8YFLogxK
U2 - 10.1111/acel.13665
DO - 10.1111/acel.13665
M3 - Article
AN - SCOPUS:85137979396
SN - 1474-9718
VL - 21
JO - Aging Cell
JF - Aging Cell
IS - 10
M1 - e13665
ER -