Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts

Baquero, Maria T.; Lostritto, Karen; Gustavson, Mark; Bassi, Kimberly; Appia, Franck; Camp, Robert L.; Molinaro, Annette M.; Harris, Lyndsay N.; Rimm, David L.

doi:10.1186/bcr2937

Cited by 36 publications

(32 citation statements)

References 23 publications

(35 reference statements)

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“…Aberrations in many of the above mentioned DUSP4 correlated genes are commonly seen in other types of breast cancer [18-20]. In our study, DUSP4 expression was associated with breast cancer outcomes for non-basal-like TNBC, including those that expressed luminal A or B signature genes.…”

Section: Discussionsupporting

confidence: 57%

Dual specificity phosphatase 4 gene expression in association with triple-negative breast cancer outcome

Baglia

Cai

Zheng

et al. 2014

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. Dual specificity phosphatase 4 (DUSP4) has recently been suggested as a potential marker of chemotherapy resistance for TNBC. Methods DUSP4 gene expression levels were measured in breast cancer tissue from 469 TNBC patients aged 20 to 75 years who participated in the Shanghai Breast Cancer Survival Study and their association with recurrence/breast cancer mortality and total mortality was evaluated. Information on breast cancer diagnosis, treatment, and disease progression was collected via medical chart review and multiple in-person follow-up surveys. A Cox regression model was applied in the data analyses. Results Over a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of the DUSP4 gene were studied and were highly correlated (r=0.76). Low DUSP4 expression levels, particularly of variant 1, were associated with both increased recurrence/breast cancer mortality and increased overall mortality. Hazard ratios with adjustment for age at diagnosis and TNM stage associated with below versus above the median expression level were 1.97 (95% confidence interval (CI): 1.27-3.05) for recurrence/breast cancer mortality and 2.09 (95% CI: 1.38-3.17) for overall mortality. Additional adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, and grade did not materially alter the observed associations. Conclusions Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors.

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Section: Discussionsupporting

confidence: 57%

Dual specificity phosphatase 4 gene expression in association with triple-negative breast cancer outcome

Baglia

Cai

Zheng

et al. 2014

Breast Cancer Res Treat

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“…Most of the studies reported that MAPT expression has prognostic value, with high expression associated with favorable patient outcome. However, at the present time, there are few studies indicating that MAPT is a predictive marker for taxane-based chemotherapy (Baquero et al 2011, Smoter et al 2011. We demonstrated that expression levels of MAPT showed positive correlation with expression levels of ER and PgR and negative correlation with expression levels of Ki67, tumor grade, and tumor size in ER-positive breast cancer.…”

Section: Discussionmentioning

confidence: 63%

miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer

Endo

Toyama

Takahashi

et al. 2012

Endocrine-Related Cancer

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Recent analyses have identified heterogeneity in estrogen receptor a (ERa)-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis, are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. In this study, expression profiles of microRNAs (miRNAs) (let-7a, miR-15a, miR-26a, miR-34a, miR-193b, and miR-342-3p). We picked up 11 genes that were potential target genes of the selected miRNAs and that were differentially expressed in ER high Ki67 low tumors and ER low Ki67 high tumors. Protein expression patterns of the selected target genes were analyzed in 256 ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its putative targets, BCL2, FOXA1, MAPT, and NAT1, were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased expression of NAT1 and FOXA1. Our results suggest that miR-1290 and its potential targets might be associated with characteristics of ER-positive breast cancer.

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“…Indeed, compounds that alter MT dynamics are an area of extensive study and several are currently used in the clinic (51). Moreover, recent work even implicates tau in the pathogenesis and prognosis of cancer (52)(53)(54)(55)(56), further supporting this mechanistic link between tau, Hsc70 and MTs. Thus, while isoform selective Hsp70 inhibitors could be best suited for neurodegenerative diseases, it is possible that compounds capable of targeting multiple Hsp70 isoforms could be most advantageous for cancer treatment.…”

Section: Discussionmentioning

confidence: 98%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts

Cited by 36 publications

References 23 publications

Dual specificity phosphatase 4 gene expression in association with triple-negative breast cancer outcome

Dual specificity phosphatase 4 gene expression in association with triple-negative breast cancer outcome

miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

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