Estrone, the major postmenopausal estrogen, binds ERa to induce SNAI2, epithelial-to-mesenchymal transition, and ER+ breast cancer metastasis.

TitleEstrone, the major postmenopausal estrogen, binds ERa to induce SNAI2, epithelial-to-mesenchymal transition, and ER+ breast cancer metastasis.
Publication TypeJournal Article
Year of Publication2022
AuthorsQureshi R, Picon-Ruiz M, Sho M, Van Booven D, de Paiva VNunes, Diaz-Ruano AB, Ince TA, Slingerland J
JournalCell Rep
Volume41
Issue7
Pagination111672
Date Published2022 Nov 15
ISSN2211-1247
Keywords17-Hydroxysteroid Dehydrogenases, Breast Neoplasms, Epithelial-Mesenchymal Transition, Estradiol, Estrogen Receptor alpha, Estrogens, Estrone, Female, Humans, Neoplasm Metastasis, NF-kappa B, Postmenopause, Snail Family Transcription Factors
Abstract

Recent work showed that the dominant post-menopausal estrogen, estrone, cooperates with nuclear factor κB (NF-κB) to stimulate inflammation, while pre-menopausal 17β-estradiol opposes NF-κB. Here, we show that post-menopausal estrone, but not 17β-estradiol, activates epithelial-to-mesenchymal transition (EMT) genes to stimulate breast cancer metastasis. HSD17B14, which converts 17β-estradiol to estrone, is higher in cancer than normal breast tissue and in metastatic than primary cancers and associates with earlier metastasis. Treatment with estrone, but not 17β-estradiol, and HSD17B14 overexpression both stimulate an EMT, matrigel invasion, and lung, bone, and liver metastasis in estrogen-receptor-positive (ER+) breast cancer models, while HSD17B14 knockdown reverses the EMT. Estrone:ERα recruits CBP/p300 to the SNAI2 promoter to induce SNAI2 and stimulate an EMT, while 17β-estradiol:ERα recruits co-repressors HDAC1 and NCOR1 to this site. Present work reveals novel differences in gene regulation by these estrogens and the importance of estrone to ER+ breast cancer progression. Upon loss of 17β-estradiol at menopause, estrone-liganded ERα would promote ER+ breast cancer invasion and metastasis.

DOI10.1016/j.celrep.2022.111672
Alternate JournalCell Rep
PubMed ID36384125
PubMed Central IDPMC9798480
Grant ListR01 CA210440 / CA / NCI NIH HHS / United States
Related Faculty: 
Tan Ince, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700