New Strategies in Metastatic Hormone Receptor–Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies

Jankowitz, Rachel C.; Oesterreich, Steffi; Lee, Adrian V.; Davidson, Nancy E.

doi:10.1158/1078-0432.ccr-16-0591

Cited by 12 publications

(16 citation statements)

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“…However, in many tamoxifen treated patients, ER activation was still detected, highlighting the demand for improved compounds and new targets [ 8 ]. In fact, since tamoxifen was approved, different ER-targeted drugs were introduced that downregulate the receptor, induce receptor degradation, or attenuate ER signaling (Table 1 ) [ 9 – 12 ]. Nevertheless, endocrine-treatment resistance remains one of the leading causes of breast cancer mortality [ 12 , 13 ].…”

Section: Breast Cancer Subtypes and Cellular Protein Quality Control mentioning

confidence: 99%

“…Yet despite the apparent specificity of these drugs, some patients remain resistant to these treatments [ 23 ], mainly due to metastasis and receptor mutations, which reduces patient survival and increases tumor relapse [ 24 ]. Moreover, ~ 10% of metastatic luminal breast cancers metastasize to the brain, and in this case the only treatment options include chemotherapy, radiation, and/or surgery [ 12 ]. Therefore, the identification of markers during early stage therapy is also of fundamental importance.…”

Section: Breast Cancer Subtypes and Cellular Protein Quality Control mentioning

confidence: 99%

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Targeting protein quality control pathways in breast cancer

Sannino¹,

Brodsky²

2017

BMC Biol

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The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival. Indeed, validated targets for anti-cancer treatments include molecular chaperones, components of the unfolded protein response, the ubiquitin-proteasome system, and autophagy. We will focus on links between breast cancer and these processes, as well as the development of drug resistance, relapse, and treatment.

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Section: Breast Cancer Subtypes and Cellular Protein Quality Control mentioning

confidence: 99%

Section: Breast Cancer Subtypes and Cellular Protein Quality Control mentioning

confidence: 99%

Targeting protein quality control pathways in breast cancer

Sannino¹,

Brodsky²

2017

BMC Biol

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“…Failure to reduce proliferation after 2 weeks of endocrine treatment [16, 35] may well identify patients that are innately resistant; however, acquired resistance remains a greater challenge in terms of identifying biomarkers and appropriate alternative or combination therapies [36]. Many of the transcriptomic changes identified in long-term treated dormant tumours are shared by some, but not all resistant tumours, providing further evidence of resistance heterogeneity [37] where dormant tumours share similar molecular changes, but there are a variety of escape mechanisms that lead to acquired resistance.…”

Section: Discussionmentioning

confidence: 99%

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

Selli

Turnbull

Pearce

et al. 2018

Preprint

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BackgroundThe risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate, previous efforts have been limited to in vitro or in vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant endocrine treatment were characterised as a novel clinical model.MethodsConsecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor, letrozole, therapy were subjected to transcriptomic and proteomic analysis, representing before (≤0), early-on (13-120 days) and long-term (>120 days) neoadjuvant letrozole treatment. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”.ResultsChanges in gene expression in dormant tumours begin early and become more pronounced at later timepoints. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared to dormant tissues after extended letrozole treatment.ConclusionsThis is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients supporting a potential role for therapy targeted at these epigenetic alterations in the management of endocrine resistant breast cancer.

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“…Hence, developing new therapeutic strategies are essential . So there remains a need for more beneficial and less cytotoxic treatments . However, the dose needs to control these tumors is high .…”

Section: Introductionmentioning

confidence: 99%

Effect of resveratrol on the radiosensitivity of 5‐FU in human breast cancer MCF‐7 cells

Aghamiri

Jafarpour

Zandsalimi

et al. 2019

J of Cellular Biochemistry

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The aim of this study was to assess the efficacy of resveratrol (Res) on radiosensitivity of 5‐fluorouracil (5‐FU) in the spheroid culture of MCF‐7 breast cancer cell line using colony formation examination. Spheroids on day 9 with 300 µm diameters were treated with 20 µM resveratrol and/or 1 µM 5‐FU for one volume doubling time (VDT) (42 hours) and then irradiated with 2 Gy gamma radiation (60Co) in various groups. Then the viability of the cells and clonogenic ability were acquired by blue dye exclusion and colony formation assay, respectively. The population doubling time in the monolayer culture and the VDT of spheroid culture was 22.48 ± 0.23 hours and 42 ± 0.63 hours respectively. None of the drugs and combination of them had any effect on the viability of cells. The combination treatment of 5‐FU+Res+ radiation significantly reduced the colony formation ability of spheroid cells in comparison with each treatment alone. Our results indicated that resveratrol can significantly decrease colony number of breast cancer spheroid cells treated with 5‐FU in combination with gamma‐rays. Thus, resveratrol as a hypoxia‐inducible factor‐1‐alpha inhibitor increased the radiosensitization of breast cancer spheroid cells.

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New Strategies in Metastatic Hormone Receptor–Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies

Cited by 12 publications

References 50 publications

Targeting protein quality control pathways in breast cancer

Targeting protein quality control pathways in breast cancer

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

Effect of resveratrol on the radiosensitivity of 5‐FU in human breast cancer MCF‐7 cells

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