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Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples
Published on: October 2, 2020
Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity
Bruno M Simões1, Ciara S O'Brien1, Rachel Eyre1
1Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
Abstract:
Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
Insights
Anti-estrogen therapies for breast cancer (BC) can unexpectedly boost cancer stem cell (CSC) activity via JAG1-NOTCH4 signaling. Targeting NOTCH4 may overcome this resistance, improving treatment outcomes for ER+ breast cancers.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Estrogen receptor-positive (ER+) breast cancers often develop resistance to endocrine therapies.
- Cancer stem cells (CSCs) are implicated in treatment resistance and tumor recurrence.
Purpose of the Study:
- To investigate the impact of anti-estrogen therapy on breast cancer stem cell (BCSC) activity.
- To elucidate the role of JAG1-NOTCH4 signaling in mediating endocrine resistance.
- To evaluate NOTCH4 inhibition as a strategy to overcome resistance.
Main Methods:
- Treatment of patient-derived samples and xenograft (PDX) models with tamoxifen or fulvestrant.
- Analysis of BCSC activity, ALDH1 expression, and NOTCH4/HES/HEY gene signatures.
- Assessment of NOTCH4 inhibition effects on BCSC activity in resistant models.
Main Results:
- Short-term anti-estrogen treatment increased BCSC activity through JAG1-NOTCH4 activation.
- High ALDH1 and a NOTCH4/HES/HEY signature predicted tamoxifen resistance.
- NOTCH4 targeting reversed anti-estrogen-induced BCSC activity and reduced it in acquired resistance models.
Conclusions:
- BCSC activity and NOTCH4 signaling are key predictors of de novo and acquired tamoxifen resistance.
- Combining endocrine therapy with JAG1-NOTCH4 inhibition offers a promising strategy to overcome resistance in ER+ breast cancers.
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