Title | Estrone, the major postmenopausal estrogen, binds ERa to induce SNAI2, epithelial-to-mesenchymal transition, and ER+ breast cancer metastasis. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Qureshi R, Picon-Ruiz M, Sho M, Van Booven D, de Paiva VNunes, Diaz-Ruano AB, Ince TA, Slingerland J |
Journal | Cell Rep |
Volume | 41 |
Issue | 7 |
Pagination | 111672 |
Date Published | 2022 Nov 15 |
ISSN | 2211-1247 |
Keywords | 17-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. |
DOI | 10.1016/j.celrep.2022.111672 |
Alternate Journal | Cell Rep |
PubMed ID | 36384125 |
PubMed Central ID | PMC9798480 |
Grant List | R01 CA210440 / CA / NCI NIH HHS / United States |
Related Faculty:
Tan Ince, M.D., Ph.D.