Overcoming endocrine resistance in breast cancer: role of the PI3K and the mTOR pathways

Kurian, Sobha; Abraham, Jame

doi:10.1586/era.12.173

Cited by 17 publications

(13 citation statements)

References 20 publications

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“…53). Furthermore, PI3K-Akt-mTOR pathway has also been implicated in endocrine drug resistance (54). The INrf2:Nrf2 system identified in the current report is a novel mechanism of AI drug resistance but is also related to the above mentioned mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Khatri

Shah

Guha

et al. 2015

Molecular Cancer Therapeutics

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Aromatase inhibitors (AIs) are effective drugs that reduce or eliminate hormone sensitive breast cancer. However, despite their efficacy, resistance to these drugs can occur in some patients. The INrf2 (Keap1):Nrf2 complex serves as a sensor of drug/radiation-induced oxidative/electrophilic stress. INrf2 constitutively suppresses Nrf2 by functioning as an adapter protein for the Cul3/Rbx1-mediated ubiquitination/degradation of Nrf2. Upon stress, Nrf2 dissociates from INrf2, is stabilized, translocates to the nucleus, and coordinately induces a battery of cytoprotective gene expression. Current studies investigated the role of Nrf2 in AI resistance. RT-PCR and immunoblot assays showed that AI-resistant breast cancer LTLTCa and AnaR cells express lower INrf2 and higher Nrf2 protein levels, as compared to drug sensitive MCF-7Ca and AC1 cells, respectively. The increase in Nrf2 was due to lower ubiquitination/degradation of Nrf2 in AI-resistant cells. Higher Nrf2-mediated levels of biotransformation enzymes, drug-transporters and anti-apoptotic proteins contributed to reduced efficacy of drugs and aversion to apoptosis that led to drug resistance. shRNA inhibition of Nrf2 in LTLTCa (LTLTCa-Nrf2KD) cells reduced resistance and sensitized cells to AI exemestane. Interestingly, LTLTCa-Nrf2KD cells also showed reduced levels of aldehyde dehydrogenase, a marker of Tumor-Initiating Cells and significantly decreased mammosphere formation, as compared to LTLTCa-Vector control cells. The results together suggest that persistent AI treatment down-regulated INrf2 leading to higher expression of Nrf2 and Nrf2 regulated cytoprotective proteins that resulted in increased AI drug resistance. These findings provide a rationale for the development of Nrf2 inhibitors to overcome resistance and increase efficacy of AI.

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Section: Discussionmentioning

confidence: 99%

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Khatri

Shah

Guha

et al. 2015

Molecular Cancer Therapeutics

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“…Responses with tamoxifen are not durable, with mean response durations of only 9 to 12 months in metastatic BC. 34 Similarly, resistance has been observed with AIs within 1–2 years. 34 Treatment options are notably limited in patients with visceral metastases, particularly in those whose disease has progressed during or after nonsteroidal AI treatment.…”

Section: Resistance To Endocrine Therapymentioning

confidence: 79%

Management of patients with hormone receptor–positive breast cancer with visceral disease: challenges and treatment options

Harb

2015

CMAR

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Endocrine therapy is an important treatment option for women with hormone receptor–positive (HR+) advanced breast cancer (ABC), yet many tumors are either intrinsically resistant or develop resistance to these therapies. Treatment of patients with ABC presenting with visceral metastases, which is associated with a poor prognosis, is also problematic. There is an unmet need for effective treatments for this patient population. Although chemotherapy is commonly perceived to be more effective than endocrine therapy in managing visceral metastases, patients who are not in visceral crisis might benefit from endocrine therapy, avoiding chemotherapy-associated toxicities that might affect quality of life. To improve outcomes, several targeted therapies are being investigated in combination with endocrine therapy for patients with endocrine-resistant, HR+ ABC. Although available data have considered patients with HR+ ABC as a whole, there are promising data from a prespecified analysis of a Phase III study of everolimus (Afinitor®), a mammalian target of rapamycin (mTOR) inhibitor, in combination with exemestane (Aromasin®) in patients with visceral disease progressing after nonsteroidal aromatase inhibitor therapy. In this review, challenges and treatment options for management of HR+ ABC with visceral disease, including consideration of therapeutic approaches undergoing clinical investigation, will be assessed.

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“…PI3K-AKT activation in response to growth factors potentiates ERα transcriptional activity (9, 10), suggesting positive cross-talk between E2 and the PI3K-AKT pathway. Clinical studies in ER + breast cancer patients have shown that PI3K-AKT activation underlies acquired resistance to anti-E2 or tamoxifen treatment (11). Indeed, clinicians are investigating if PI3K inhibitors can reverse anti-E2 resistance (12,13).…”

mentioning

confidence: 99%

Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway

Gorrini

Gang

Bassi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissuespecific nature of BRCA1's tumor suppression is obscure. We previously showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of NRF2-dependent antioxidant genes in various E2-responsive cell types. Like NRF2 accumulation triggered by oxidative stress, E2-induced NRF2 accumulation depends on phosphatidylinositol 3-kinase-AKT activation. Pretreatment of mammary epithelial cells (MECs) with the phosphatidylinositol 3-kinase inhibitor BKM120 abolishes the capacity of E2 to increase NRF2 protein and transcriptional activity. In vivo the survival defect of BRCA1-deficient MECs is rescued by the rise in E2 levels associated with pregnancy. Furthermore, exogenous E2 administration stimulates the growth of BRCA1-deficient mammary tumors in the fat pads of male mice. Our work elucidates the basis of the tissue specificity of BRCA1-related tumor predisposition, and explains why oophorectomy significantly reduces breast cancer risk and recurrence in women carrying BRCA1 mutations.breast cancer | reactive oxygen species | hormones | PTEN B RCA1 mutations promote tumor formation almost exclusively in hormone-responsive tissues such as breast and ovary (1). It has been proposed that the steroid hormone estrogen (E2) increases the survival of BRCA1-deficient cells in these tissues, favoring tumorigenesis (2). However, why BRCA1-mutated breast and ovarian epithelial cells have a survival advantage remains unclear.E2 regulates cell differentiation, growth, and survival in a broad range of human tissues. The most abundant and potent E2 circulating in the body is 17β-estradiol. In its classical mechanism of action, E2 diffuses into the cells and binds to two nuclear E2 receptors (ERs), ERα and ERβ, which act as transcription factors and influence gene expression (3). Nonclassical mechanisms involve E2 binding to plasma membrane-associated ER proteins. An example of the latter is the phosphatidylinositol 3-kinase (PI3K) that is known to mediate E2-induced cell survival and proliferation (4). In female mice, E2 administration activates PI3K in ovarian granulosa cells (5). In vitro, E2 treatment of ER + MCF7 human breast cancer cells stimulates the serine/threonine-protein kinase, AKT, and leads to increased glucose uptake (6) and cell cycle progression (7). E2-induced AKT activation is also involved in axonal growth and neuronal morphogenesis (8). PI3K-AKT activation in response to growth factors potentiates ERα transcriptional activity (9, 10), suggesting positive cross-talk between E2 and the PI3K-AKT pathway. Clinical studies in ER + breast cancer patients have shown that PI3K-AKT activation underlies acquired resistance to anti-E2 or tamoxifen treatment (11). Indeed, clinicians...

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Overcoming endocrine resistance in breast cancer: role of the PI3K and the mTOR pathways

Cited by 17 publications

References 20 publications

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Management of patients with hormone receptor–positive breast cancer with visceral disease: challenges and treatment options

Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway

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Overcoming endocrine resistance in breast cancer: role of the PI3K and the mTOR pathways

Cited by 17 publications

References 20 publications

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer

Management of patients with hormone receptor&ndash;positive breast cancer with visceral disease: challenges and treatment options

Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway

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Management of patients with hormone receptor–positive breast cancer with visceral disease: challenges and treatment options