Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mills, John; Rutkovsky, Alex; Giordano, Antonio

doi:10.1016/j.coph.2018.04.009

Cited by 123 publications

(92 citation statements)

References 57 publications

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“…The phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway is a key signaling driver of cellular proliferation and survival of cancer cells. Dysregulation and activation of this pathway can drive tumorigenesis of ER+/HER2− breast cancers and is associated with resistance to anti-estrogen-targeted therapies [17,18]. Previous studies in our laboratory have demonstrated that inhibitors of the PI3K/AKT/mTOR pathway have selective activity in ER+ breast cancer cell lines carrying activating mutations in PIK3CA [19,20].…”

Section: Introductionmentioning

confidence: 96%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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Background: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/ HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

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Section: Introductionmentioning

confidence: 96%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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“…Despite its wide use for the treatment of breast cancer, a third of patients with breast cancer develop resistance to tamoxifen, which results in tumor progression (24). Additionally, TAMR breast cancer is more prone to invasion and metastasis (6), thus identifying the mechanisms underlying drug-resistant tumor metastasis, as well as novel therapeutic strategies is critical to improve patient survival.…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates lncRNA H19‑induced epithelial‑mesenchymal transition in tamoxifen‑resistant breast cancer cells

et al. 2020

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The H19 long non-coding RNA is involved in the development of tamoxifen resistance in breast cancer. However, the relationship between H19 and the metastatic potential and treatment options for tamoxifen-resistant (TAMR) breast cancer is not completely understood. Curcumin inhibits cellular proliferation, migration and invasiveness in several cancer types, including pancreatic cancer, breast cancer and chronic myeloid leukemia. The present study aimed to investigate the role of H19 in MCF-7/TAMR cell epithelial-mesenchymal transition (EMT), migration and invasiveness, and to assess the ability of curcumin to inhibit H19-mediated effects. Reverse transcription-quantitative PCR and western blot analysis were conducted to detect the gene or protein expression. Cell Counting Kit-8, wound healing and Transwell invasion assays were performed to estimate the capabilities of cell viability, invasion and migration. H19 overexpression enhanced MCF-7/TAMR cell EMT, invasion and migration by upregulating Snail. Furthermore, curcumin notably decreased the expression levels of epithelial marker E-cadherin and markedly increased the expression levels of mesenchymal marker N-cadherin in MCF-7/TAMR cells compared with the control group. In addition, following treatment with curcumin for 48 h, H19 expression was decreased in a dose-dependent manner. Moreover, curcumin treatment for 48 h significantly attenuated H19-induced alterations in N-cadherin and E-cadherin expression levels. Curcumin also prevented H19-induced invasion and migration. The present study indicated that H19 may serve as a promoting factor of EMT, invasion and migration in MCF-7/TAMR cells, suggesting that curcumin may prevent H19-associated metastasis. Therefore, curcumin may serve as a promising therapeutic drug for patients with TAMR breast cancer.

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“…The observed endocrine resistance in a proportion of patients with this kind of cancer can be at least partly explained by the dysregulation in the expression of miRNAs/lncRNAs. Resistance to endocrine therapies is complicated process that involves epigenetic alterations in the ESR1 gene, alternative splicing events, post-translational alterations and altered recruitment of co-regulators of ER; it also affects the tumor milieu and several other mechanisms [120]. Almost all aspects of this complex process can be modulated by non-coding RNAs.…”

Section: Discussionmentioning

confidence: 99%

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

Taheri

Shoorei

Dinger

et al. 2020

Cancers

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Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders.

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Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Cited by 123 publications

References 57 publications

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Curcumin attenuates lncRNA H19‑induced epithelial‑mesenchymal transition in tamoxifen‑resistant breast cancer cells

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

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Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Cited by 123 publications

References 57 publications

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Curcumin attenuates lncRNA H19‑induced epithelial‑mesenchymal transition in&nbsp;tamoxifen‑resistant breast cancer cells

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

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Curcumin attenuates lncRNA H19‑induced epithelial‑mesenchymal transition in tamoxifen‑resistant breast cancer cells