mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells

Karthik, Govindasamy-Muralidharan; Ma, Ran; Lövrot, John; Kis, Lóránd; Lindh, Claes; Blomquist, Lennart; Fredriksson, Irma; Bergh, Jonas; Hartman, Johan

doi:10.1016/j.canlet.2015.07.017

Cited by 46 publications

(42 citation statements)

References 74 publications

(59 reference statements)

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“…As a consequence of ERα absence, treatment with its agonist PPT did not affect the number of mammospheres, nor did tamoxifen or fulvestrant. We have recently shown that tamoxifen activates mTOR-regulated ribosomal synthesis and is insufficient to inhibit proliferation in BSCs (32). Our findings shed light on the incapability of current endocrine agents to completely eradicate all tumor cells as a proportion of breast cancers relapse after or during adjuvant endocrine therapy.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells

Karthik

Lövrot

et al. 2017

JNCI: Journal of the National Cancer Institute

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Background: Breast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer. Methods: We characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ERβ-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n = 4 or 5 per group) were used to study the role of ERs during tumorigenesis. Results: We identified an absence of ERα but upregulation of ERβ in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ERβ caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ERβ-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ERβ (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts. Conclusion: We identify ERβ as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells

Karthik

Lövrot

et al. 2017

JNCI: Journal of the National Cancer Institute

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“…Further, in mouse xenograft models of breast cancer, the tyrosine kinase inhibitor sunitinib was found to reduce tumor volume of triple-negative MDA-MB-468 cells but increased the frequency of breast cancer stem cells (Chinchar et al , 2014). Importantly, inhibitors of the metabolic pathway-associated mTOR were found to counteract tamoxifen-induced activation of breast cancer cells (Karthik et al , 2015), suggesting that resistance to temoxifen is associated with metabolic dysregulation. The enhanced expression of PTEN in Dox-treated HFDO tumors appears counter-intuitive to its tumor suppressor role and the recent report that decreased PTEN function is associated with increased resistance of breast cancer cells to doxorubicin (Steelman et al , 2008).…”

Section: Discussionmentioning

confidence: 99%

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice

Montales

Melnyk

Liu

et al. 2016

Endocrine-Related Cancer

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The emerging links between breast cancer and metabolic dysfunctions spawned by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient’s metabolic status to affect disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well-defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1-transgenic offspring exposed to a metabolically-compromised environment imposed by maternal high-fat diet; control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, when compared to control diet exposure. However, doxorubicin-treated tumors from high-fat diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1), and basal stem cell-like (CD29hiCD24+) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations [CD29hiCD24+, CD29loCD24+, CD29hiCD24+Thy1+] in tumors from high-fat diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced mammosphere-formation ability and decreased apoptosis, relative to doxorubicin only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny and may inform clinical management of disease.

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“…For breast cancer, concurrent use of everolimus with trastuzumab resulted in greater reduction in the in vitro tumorigenicity as well as in vivo growth of patient derived and BT474 CSCs than either agent alone (Zhu et al, 2012). Addition of rapamycin, everolimus, or PF-04691502 to tamoxifen therapy also reduced mammosphere formation of patient derived CSCs through ameliorating tamoxifen induced mTOR activation in these CSCs (Karthik et al, 2015). Likewise, in glioblastoma, pretreatment with AZD2014 followed by radiation or combined therapy of BEZ235 with radiation increased the radiosensitivity of glioblastoma CSCs in vitro (Wang W.-J.…”

Section: Mtor Inhibitors For Modulating Mtor Activity To Combat Cancementioning

confidence: 99%

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

et al. 2016

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The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.

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mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells

Cited by 46 publications

References 74 publications

Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells

Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

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