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High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer


Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including antiestrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer.

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Fig. 1: Breast cancer cells that therapeutically respond to E2 are ER-dependent despite estrogen deprivation.
Fig. 2: Overexpression of ER induces estrogen-independent ER signaling and resistance to estrogen deprivation.
Fig. 3: Overexpression of ER converts E2 from a growth promoter to a growth suppressor.
Fig. 4: Therapeutic response to E2 is accompanied by hyperactivation of ER transcriptional activity.
Fig. 5: Resistance to E2 therapy is associated with downregulation of ER levels and activity.
Fig. 6: Cycling E2 and estrogen deprivation is an effective strategy for maintaining long-term tumor control.


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This work was supported by Susan G. Komen (CCR1533084 to TWM) and NIH (R01CA200994 and R01CA211869 to TWM, F31CA243409 to NAT, Dartmouth College Norris Cotton Cancer Center Support Grant P30CA023108). We thank the following Norris Cotton Cancer Center Shared Resources for their support: Mouse Modeling; Pathology; Biostatistics; Microscopy; Genomics.

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Correspondence to Todd W. Miller.

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Traphagen, N.A., Hosford, S.R., Jiang, A. et al. High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer. Oncogene 40, 3408–3421 (2021).

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