Overcoming Endocrine Resistance in Breast Cancer

Hanker, Ariella B.; Sudhan, Dhivya R.; Arteaga, Carlos L.

doi:10.1016/j.ccell.2020.03.009

Cited by 529 publications

(501 citation statements)

References 197 publications

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“…All animal studies were ethically conducted in accordance with our approved Institutional Animal Care and Use Committee (IACUC) protocols #2018-0005 and #2018-0006. For the comparison of time to tumor formation between HCI-013 and HCI-013EI in the presence vs. absence of supplemental estrogen pellets, twenty four (24) 5-6 week-old intact (non-ovariectomized) female non-obese diabetic, severe combined immunodeficient mice (NOD.CB17-Prkdcscid/NCrCrl, purchased from Charles River, Wilmington, MA) were orthotopically implanted in the right 4th mammary gland with a single 1-3 mm 3 PDX fragment per mouse as follows: HCI-013EI (n=6); HCI-013EI+E2 (n=6); HCI-013 (n=6); HCI-013+E2 (n=6). "+E2" denotes co-implantation of a 1 mg estrogen pellet under the skin on the back between the shoulder blades.…”

Section: Hci-013 and Hci-013ei Xenograft Experimentsmentioning

confidence: 99%

“…Mice were followed until measurable tumor development (by calipers), and data are presented as a survival plot with n=6 mice per group. For treatment studies of HCI-013EI tumors, forty eight (48) 5-6 week-old intact (non-ovariectomized) female mice were orthotopically implanted in the right 4th mammary gland with a single 1-3 mm 3 HCI-013EI PDX fragment per mouse without estrogen supplementation, then followed until tumors reached ~100 mm 3 before enrollment to one of the four (4) treatment arms: control (n=8), 10 mg Fulvestrant in castor oil SQ (2 5-mg injections per week, n=9), 10 mg/kg Riluzole PO in corn oil (5 days per week, n=9), or the combination (n=9). Mice were monitored for tumor growth (measured by calipers) and body weight twice per week.…”

Section: Hci-013 and Hci-013ei Xenograft Experimentsmentioning

confidence: 99%

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Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

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BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsIn the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone.ConclusionsThese findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

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Section: Hci-013 and Hci-013ei Xenograft Experimentsmentioning

confidence: 99%

Section: Hci-013 and Hci-013ei Xenograft Experimentsmentioning

confidence: 99%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

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“…This work was supported in part by Grants-in-Aid for Scientific Research from the Aichi Cancer Research Foundation (grant no. [2][3][4][5][6][7][8][9][10][11][12]. TH was also supported by funding from a Grant-in-Aid for Young Scientists (B), 2017-2019 (No.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…AIs generally have fewer side effects and significantly improved efficacy when compared to the currently used breast cancer treatments. Much of the recent research on AIs focuses on determining the mechanisms of resistance to these inhibitors [9][10][11][12].…”

mentioning

confidence: 99%

Upregulation of CIP2A in estrogen depletion‐resistant breast cancer cells treated with low‐dose everolimus

et al. 2020

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Everolimus (EVE), an inhibitor of mammalian target of rapamycin, is an emerging second-line therapeutic option for hormone therapy-resistant breast cancers. However, some patients do not respond to EVE, whereas in others it exacerbates the disease. Cellular inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that can promote cancer cell growth and apoptosis resistance. Although CIP2A is upregulated in hormone-related cancers, such as breast cancer, little is known about potential anti-tumor effects of downregulating CIP2A. As a model to study the resistance of breast cancer cells to hormone treatment, we previously established clones of long-term estrogen depletion-resistant MCF-7 (LTED) cells. Here, we selected three clones highly responsive to EVE and three clones poorly responsive to EVE. When cells were treated with EVE, CIP2A mRNA expression was decreased in highly responsive EVE clones (DC-cells) whereas it was increased in poorly responsive EVE clones (IC-cells). Using Kaplan-Meier survival plots, we report that high expression of CIP2A was associated with significantly reduced overall survival in patients with luminal A breast cancer. In IC-cells, cell growth was enhanced upon EVE treatment whereas an EVE range of 0.1-100 nM decreased growth in DC-cells. The mRNA expression of genes involved in epithelial-mesenchymal transition (EMT) such as CDH1, CLDN3, and CK19 was significantly decreased in IC-cells, but remained unchanged in DC-cells. These findings highlight a relationship between CIP2A and EMT in the intrinsic resistance of hormone therapy-resistant breast cancers to EVE.

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“…Numerous studies have shown that universal resistance to chemotherapeutic drugs is the most signi cant obstacle to successful BRCA treatment [5][6][7]. Current rst-line chemotherapeutic drugs include Cytoxan, Adriamycin, and Tamoxifen.…”

Section: Introductionmentioning

confidence: 99%

Inferences From Dysregulated Long Non-Coding RNA-Mediated Competing Endogenous RNAs in Various Chemotherapy Drugs and Evaluation of Drug Response in Breast Cancer

Zhang¹,

Li²,

Zhang³

et al. 2020

Preprint

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Backgroud: Differences in individual drug response, especially drug resistance, present an obstacle to the treatment of breast cancer (BRCA). Thus, the ability to predict drug response would contribute to developing novel treatment strategies. Accumulating evidence have suggested that tumor molecular profiles and drug response data provide opportunities and challenges for the discovery of new molecular characteristics and mechanisms of drug response in BRCA. Methods: In the present study, an integrated pipeline was developed to explore drug response-related long non-coding RNA (lncRNA)-mediated competing endogenous RNAs (ceRNAs) motifs in BRCA. Results: Drug response-specific ceRNAs indicated that lncRNAs play an essential role in various drug treatments for BRCA. Several key drug-resistant and -sensitive dysregulated ceRNAs were identified in Adriamycin, Cytoxan, and Tamoxifen. The interactions in these ceRNAs showed strong correlations in BRCA. Most drug response-related dysregulated ceRNAs were only present in one kind of drug. A number of drug response-related ceRNAs presented diverse dysregulation patterns. We also extracted some key drug response-related lncRNAs, such as HCP5 and FAM182A. These lncRNAs were associated with certain cancer hallmarks and survival in BRCA. Conclusions: Ultimately, understanding the underlying lncRNA-mediated ceRNAs in drug responses will facilitate improved individual reactions to chemotherapy and overall outcomes of BRCA treatment.

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Overcoming Endocrine Resistance in Breast Cancer

Cited by 529 publications

References 197 publications

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Upregulation of CIP2A in estrogen depletion‐resistant breast cancer cells treated with low‐dose everolimus

Inferences From Dysregulated Long Non-Coding RNA-Mediated Competing Endogenous RNAs in Various Chemotherapy Drugs and Evaluation of Drug Response in Breast Cancer

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