NRF2-dependent metabolic reprogramming is required for tumor recurrence following oncogene inhibition

2019 ◽  
Author(s):  
Douglas B. Fox ◽  
Ryan Lupo ◽  
Laura C. Noteware ◽  
Rachel Newcomb ◽  
Juan Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Residual Disease ◽  
Cancer Recurrence ◽  
Cellular Metabolism ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Recurrent Tumors ◽  
Recurrent Breast

SummaryOncogenic signaling pathways both directly and indirectly regulate anabolic metabolism, and this is required for tumor growth. Targeted therapies that inhibit oncogenic signaling have dramatic impacts on cellular metabolism. However, it is not known whether the acquisition of resistance to these therapies is associated with – or driven by – alterations in cellular metabolism. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during residual disease, and after tumor recurrence. We found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during residual disease and tumor recurrence, and NRF2 was both sufficient to promote tumor recurrence, and necessary for recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors induced metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. Finally, this NRF2-driven metabolic state rendered recurrent tumor cells sensitive to glutaminase inhibition, suggesting that NRF2-high recurrent tumors can be therapeutically targeted. Together, these data provide evidence that NRF2-driven metabolic reprogramming is required for breast cancer recurrence following oncogene inhibition.SignificanceAlthough tumor recurrence is the leading cause of mortality in breast cancer, the cellular properties that allow tumor cells to evade therapy and form recurrent tumors remain largely uncharacterized. Similarly, very little is known about how tumor metabolism changes following therapy, or whether alterations in cellular metabolism drive tumor recurrence. In this study, we identify the antioxidant transcription factor NRF2 as a critical positive regulator of breast cancer recurrence. We find that NRF2-dependent metabolic reprogramming is both sufficient and required to promote tumor recurrence. Additionally, we demonstrate that the NRF2-driven metabolic state renders recurrent tumors sensitive to glutaminase inhibitors, suggesting a novel therapeutic approach for the treatment of recurrent breast cancer.

scholarly journals RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

2019 ◽  
Author(s):  
Chao-Chieh Lin ◽  
Nathaniel Mabe ◽  
Yi-Tzu Lin ◽  
Wen-Hsuan Yang ◽  
Xiaohu Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Tumor Recurrence ◽  
Cancer Recurrence ◽  
Breast Cancer Recurrence ◽  
Recurrent Tumor ◽  
Breast Tumor Cells ◽  
Recurrent Tumors ◽  
Recurrent Breast

AbstractThe molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo programmed necrosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

scholarly journals The effect of smoking on biological change of recurrent breast cancer

2020 ◽  
Author(s):  
Koji Takada ◽  
Shinichiro Kashiwagi ◽  
Yuka Asano ◽  
Wataru Goto ◽  
Rika Kouhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Smoking History ◽  
Her2 Expression ◽  
Recurrent Tumors ◽  
Recurrent Breast

Abstract Background: The selection of treatment for a patient with breast cancer largely relies on the cancer subtype. However, this process is complicated by changes in tumor biology at relapse. Smoking has been identified as a risk factor for breast cancer. The direct effect of a tobacco component delivered via blood circulation on the mammary gland tissue and subsequent DNA damage have been proposed to explain the association between cigarette smoking and breast cancer carcinogenesis. This postulation is supported by both tissue culture and animal studies demonstrating that the associated DNA damage further alters breast cancer cells, as indicated by an increased proliferative capacity and malignant transformation. In this study, we aimed to explore the relationship between changes in Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) each receptor at recurrence, and smoking and the prognosis after recurrence.Methods: This retrospective study included 989 patients with primary breast cancer who developed relapse after surgery and 50 patients who underwent regenerative biopsy or surgery from December 2007 to March 2018. ER, PgR, and HER2 expression in the primary and recurrent lesions was evaluated using immunohistochemistry, and the correlations of these expression patterns with smoking history (pack-years) were examined.Results: When ER was evaluated in recurrent tumors, negative and positive conversions were recognized in 3 (6.0%) and 1 patient (2.0%), respectively. When PgR was evaluated, negative conversion was recognized in 15 patients (30.0%). When HER2 was evaluated, positive conversion was recognized in 6 patients (12.0%). Consequently, we observed a change in the intrinsic subtype in in 5 patients with recurrent tumors (10.0%). Although most clinical factors were not correlated with smoking, a positive conversion of HER2 in recurrence was significantly more frequent among smokers than among non-smokers (p=0.024).Conclusions: Biological changes during breast cancer recurrence should be given careful clinical consideration because they affect treatment after recurrence. Our results suggest that smoking may induce increased HER2 expression in recurrent breast tumors.

scholarly journals CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Andrea Walens ◽  
Ashley V DiMarco ◽  
Ryan Lupo ◽  
Benjamin R Kroger ◽  
Jeffrey S Damrauer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Immune Cell ◽  
Cancer Recurrence ◽  
Residual Tumor ◽  
Breast Cancer Recurrence ◽  
Immune Cell Infiltration ◽  
Conditional Mouse Model

Over half of breast-cancer-related deaths are due to recurrence 5 or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

scholarly journals Cellular dormancy in minimal residual disease following targeted therapy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jason R. Ruth ◽  
Dhruv K. Pant ◽  
Tien-chi Pan ◽  
Hans E. Seidel ◽  
Sanjeethan C. Baksh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Tumor Cells ◽  
Human Breast Cancer ◽  
Residual Disease ◽  
Residual Tumor ◽  
Human Breast ◽  
Primary Tumors ◽  
Oncogenic Pathway ◽  
Recurrent Tumors

Abstract Background Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. Methods To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. Results We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. Conclusions Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

scholarly journals G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program

2020 ◽  
Author(s):  
Nathaniel W. Mabe ◽  
Shayna E. Wolery ◽  
Rachel Newcomb ◽  
Ryan C. Meingasner ◽  
Brittany A. Vilona ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Recurrence ◽  
Cancer Recurrence ◽  
Recurrent Breast Cancer ◽  
Genetically Engineered ◽  
Breast Cancer Recurrence ◽  
Gene Promoters ◽  
Genetic Ablation ◽  
Recurrent Tumors ◽  
Genetically Engineered Mouse Model

AbstractEpigenetic dysregulation is a common feature of cancer, and is thought to underlie many aspects of tumor progression. Using a genetically engineered mouse model of breast cancer recurrence, we show that recurrent mammary tumors undergo widespread epigenomic and transcriptional alterations, and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including TNF, through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that epigenetic rewiring – specifically G9a-mediated silencing of pro-necroptotic proteins – is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.

scholarly journals CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors

2019 ◽  
Author(s):  
Andrea Walens ◽  
Ashley V. DiMarco ◽  
Ryan Lupo ◽  
Benjamin R. Kroger ◽  
Jeffrey S. Damrauer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Immune Cell ◽  
Cancer Recurrence ◽  
Residual Tumor ◽  
Breast Cancer Recurrence ◽  
Immune Cell Infiltration ◽  
Conditional Mouse Model

ABSTRACTOver half of breast cancer related deaths are due to recurrence five or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

scholarly journals The effect of smoking on biological change of recurrent breast cancer

2020 ◽  
Author(s):  
Koji Takada ◽  
Shinichiro Kashiwagi ◽  
Yuka Asano ◽  
Wataru Goto ◽  
Rika Kouhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Smoking History ◽  
Her2 Expression ◽  
Recurrent Tumors ◽  
Recurrent Breast

Abstract Background The selection of treatment for a patient with breast cancer largely relies on the cancer subtype. However, this process is complicated by changes in tumor biology at relapse. Smoking has been identified as a risk factor for breast cancer. The direct effect of a tobacco component delivered via blood circulation on the mammary gland tissue and subsequent DNA damage have been proposed to explain the association between cigarette smoking and breast cancer carcinogenesis. This postulation is supported by both tissue culture and animal studies demonstrating that the associated DNA damage further alters breast cancer cells, as indicated by an increased proliferative capacity and malignant transformation. In this study, we aimed to explore the relationship between changes in Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) each receptor at recurrence, and smoking and the prognosis after recurrence. Methods This retrospective study included 989 patients with primary breast cancer who developed relapse after surgery and 50 patients who underwent regenerative biopsy or surgery from December 2007 to March 2018. ER, PgR, and HER2 expression in the primary and recurrent lesions was evaluated using immunohistochemistry, and the correlations of these expression patterns with smoking history (pack-years) were examined. Results When ER was evaluated in recurrent tumors, negative and positive conversions were recognized in 3 (6.0%) and 1 patient (2.0%), respectively. When PgR was evaluated, negative conversion was recognized in 15 patients (30.0%). When HER2 was evaluated, positive conversion was recognized in 6 patients (12.0%). Consequently, we observed a change in the intrinsic subtype in in 5 patients with recurrent tumors (10.0%). Although most clinical factors were not correlated with smoking, a positive conversion of HER2 in recurrence was significantly more frequent among smokers than among non-smokers (p=0.024). Conclusions Biological changes during breast cancer recurrence should be given careful clinical consideration because they affect treatment after recurrence. Our results suggest that smoking may induce increased HER2 expression in recurrent breast tumors.

Postchemotherapy rheumatism.

1993 ◽  
Vol 11 (4) ◽  
pp. 768-770 ◽  
Author(s):  
C L Loprinzi ◽  
J Duffy ◽  
J N Ingle
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Combination Chemotherapy ◽  
Case Reports ◽  
Cancer Recurrence ◽  
Recurrent Breast Cancer ◽  
Rheumatologic Diseases ◽  
Clinical Phenomenon ◽  
Recurrent Breast

PURPOSE This report describes a previously unreported clinical phenomenon that occurs in some patients after completion of combination chemotherapy. METHODS AND RESULTS Eight case reports are presented. Affected patients developed a syndrome of myalgias/arthralgias within several months of completing cyclophosphamide/fluorouracil (5FU)-containing adjuvant combination chemotherapy for breast cancer. These symptoms did not appear to be related to cancer recurrence or any common rheumatologic disorder. The syndrome generally resolved over several months. CONCLUSION Postchemotherapy rheumatism is a syndrome of myalgias/arthralgias that usually develops 1 to 3 months after completion of adjuvant chemotherapy. Recognition of this syndrome can limit the need for extensive work-ups to exclude recurrent breast cancer or inflammatory rheumatologic diseases.

Neoadjuvant chemotherapy (NCT) in 710 patients for operable breast cancer: Comparison of 2 pathological classifications

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10502-10502
Author(s):  
F. Penault-Llorca ◽  
C. Abrial ◽  
I. Raoelfils ◽  
S. Amat ◽  
M. Mouret-Reynier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Residual Disease ◽  
Residual Tumor ◽  
Median Number ◽  
Operable Breast Cancer ◽  
Isolated Tumor Cells ◽  
Actuarial Survival

10502 Background: In a database harbouring the patients of several prospective phase II neoadjuvant trials (avcf, avcfm, fec 50–100, nem, net, tncf, taxotère/tncf, taxotere alone), clinical and pathological responses rates were studied in 710 women with stage II-III operable breast cancer treated 1982–2004. Pathological review was conducted to assess the residual disease in breast and nodes according to the 2 most used classifications in Europe: CHEVALLIER’s and SATALOFF’s (Am J Clin Oncol 1993; J Am Coll Surg 1995). Methods: Median age of the patients was 49.5 years [26–81]. Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar, 90 (13%) a lobular, 18 (2.5%) a mixed or invasive carcinoma, 36 (5%) neoplasic cells only and 11 (1.5%) another carcinoma. 25.6% of the tumours were grade III SBR, 28.3% grade 4 or 5 MSBR. The median number of NCT courses was 6 [1–9] followed by a surgery for 92%, a radiotherapy for 95%, an adjuvant chemotherapy (17%) and/or a hormonotherapy (52%). A breast evaluation was realized before, during and after NCT (Amat et al, Breast Cancer Res Treat 2005). Results: Intent to treat (n = 710), overall response rate was 68% (16% complete). The complete pathological response (pCR) rate was 14.18% according to Chevallier’s and 22.50% according to Sataloff’s classification. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes (median number:1 [0–20]). After a median follow-up of 93 months, DFS and actuarial survival at 120 months were 54.9% and 66.5%, respectively.Chevallier’s classification level 1 (pCR in breast and axilla) was the most predictive of a good DFS, with a plateau appearance near 80%. Chevallier’s classification level 2 (in situ only) and Sataloff grade A (pCR and isolated tumor cells) yielded a lesser DFS (p < 0.01). With a long follow-up, a complete pCR is the most favourable prognostic factor, followed by in situ only or isolated tumor cells, then residual tumor. Conclusions: Sataloff’s gives higher pCR figures than Chevallier’s without evidence of superior predictive value. The classification used is important to predict outcome after NCT. No significant financial relationships to disclose.

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