Co-expression Effect of LLCL2 and SLC7A5 to Predict Prognosis in ERα-Positive Breast Cancer

Abstract Lethal giant larvae homolog 2 (LLGL2) and solute carrier family 7 member 5 (SLC7A5) have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to endocrine therapy in ERα-positive breast cancer patients by using LLGL2/SLC7A5 mRNA and protein expression in long-term follow-up invasive breast cancer tissues. We identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with disease-free survival (DFS) compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer DFS and overall survival (OS) compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS, not only in all breast cancer patients, but also in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker in early breast cancer patients.

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Prognostic impact of co-expression of LLCL2 and SLC7A5 in ERα-positive breast cancer patients

10.21203/rs.3.rs-728950/v1 ◽

2021 ◽

Author(s):

Tomoka Hisada ◽

Naoto Kondo ◽

Yumi Wanifuchi-Endo ◽

Satoshi Osaga ◽

Takashi Fujita ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Endocrine Therapy ◽

Tamoxifen Therapy ◽

Adjuvant Tamoxifen ◽

Positive Trend ◽

Breast Cancer Patients ◽

Adjuvant Tamoxifen Therapy ◽

Positive Breast Cancer

Abstract Background Lethal giant larvae homolog 2 (LLGL2) functions as a promoter of tumor growth and localizes at cell junctions and membranes with solute carrier family 7 member 5 (SLC7A5) in estrogen receptor α (ERα)-positive breast cancer. LLGL2 and SLC7A5 have been reported to be involved in resistance to endocrine therapy. This study aimed to assess the effects of LLGL2/SLC7A5 co-expression in predicting prognosis and response to endocrine therapy in ERα-positive breast cancer patients. Methods The associations of clinicopathological factors with LLGL2 and SLC7A5 expression or LLGL2/SLC7A5 co-expression at the mRNA and protein level were assessed in invasive breast cancer patients with long-term follow-up. The median follow-up period was approximately10 years. Survival curves were analyzed using the Kaplan–Meier method and verified by the log-rank test. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values using stepwise linear regression. Results We identified a positive association between low mRNA expression of LLGL2 or SLC7A5 alone and longer disease-free survival (DFS) and overall survival (OS) in ERα-positive breast cancer patients, but not in ERα-negative patients. We also identified that low LLGL2/SLC7A5 mRNA co-expression (LLGL2low/SLC7A5low) was associated with longer survival compared with other combination groups in all breast cancer patients. In ERα-positive breast cancer patients, LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high and a positive trend of longer survival compared with other combination groups. We also observed that LLGL2low/SLC7A5low showed longer survival compared with LLGL2high/SLC7A5high in ERα-positive breast cancer patients receiving adjuvant tamoxifen therapy. Multivariate analysis demonstrated that LLGL2low/SLC7A5low was an independent favorable prognostic factor of both DFS and OS in ERα-positive breast cancer patients. High co-expression of LLGL2 and SLC7A5 protein showed a positive trend of shorter survival. Conclusions Our study showed that co-expression of LLGL2 and SLC7A5 mRNA is a promising candidate biomarker and suggested that the LLGL2–SLC7A5 axis may be a therapeutic target in early breast cancer patients, especially in those receiving adjuvant tamoxifen therapy.

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ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression

Molecular and Cellular Biology ◽

10.1128/mcb.00261-19 ◽

2019 ◽

Vol 39 (23) ◽

Cited By ~ 11

Author(s):

Yuichi Mitobe ◽

Kazuhiro Ikeda ◽

Takashi Suzuki ◽

Kiyoshi Takagi ◽

Hidetaka Kawabata ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Patients ◽

Endocrine Therapy ◽

Cancer Progression ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Breast Cancer Patients ◽

Er Positive ◽

Positive Breast Cancer

ABSTRACT Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.

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Activated HER-receptors in predicting outcome of ER-positive breast cancer patients treated with adjuvant endocrine therapy

The Breast ◽

10.1016/j.breast.2012.07.005 ◽

2012 ◽

Vol 21 (5) ◽

pp. 662-668 ◽

Cited By ~ 7

Author(s):

Mathilde S. Larsen ◽

Karsten Bjerre ◽

Anne E. Lykkesfeldt ◽

Anita Giobbie-Hurder ◽

Anne-Vibeke Lænkholm ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Endocrine Therapy ◽

Adjuvant Endocrine Therapy ◽

Breast Cancer Patients ◽

Er Positive ◽

Predicting Outcome ◽

Positive Breast Cancer

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Long-term follow-up of axillary node-positive breast cancer patients receiving adjuvant tamoxifen alone: patterns of recurrence

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(98)00177-1 ◽

1998 ◽

Vol 42 (1) ◽

pp. 117-123 ◽

Cited By ~ 34

Author(s):

BarbaraJ Fisher ◽

FranciscoE Perera ◽

AndrewL Cooke ◽

Abiola Opeitum ◽

Larry Stitt

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Axillary Node ◽

Breast Cancer Patients ◽

Node Positive ◽

Long Term Follow Up ◽

Patterns Of Recurrence ◽

Positive Breast Cancer

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Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0076 ◽

2008 ◽

Vol 42 (2) ◽

pp. 87-103 ◽

Cited By ~ 37

Author(s):

Sandra E Ghayad ◽

Julie A Vendrell ◽

Ivan Bieche ◽

Frédérique Spyratos ◽

Charles Dumontet ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Candidate Genes ◽

Endocrine Therapy ◽

Cell Lines ◽

Tamoxifen Treatment ◽

Cross Resistance ◽

Breast Cancer Patients ◽

Er Positive ◽

Positive Breast Cancer

Cross-resistance to molecules used in endocrine therapy is among the main challenges in the treatment of estrogen receptor-α (ERα) positive breast cancer. In this study, we used two different cell models of resistance to anti-estrogens: MVLN/CL6.7 cells and VP229/VP267 cells selected after exposure to tamoxifen respectively in vitro and in vivo to characterize a phenotype rarely observed, i.e. acquisition of cross-resistance to the pure ER antagonist fulvestrant. As MVLN/CL6.7 cells and VP229/VP267 cell lines are original and valuable models of cross-resistance to tamoxifen and fulvestrant, we examined candidate genes using a RTQ-PCR strategy to identify new biomarkers of endocrine resistance. Out of the 26 candidate genes tested, 19 displayed deregulation of expression at the basal level in at least one of the two resistant cell lines. Eight genes (TACC1, NOV, PTTG1, MAD2L1, BAK1, TGFB2, BIRC5, and CCNE2) were significantly overexpressed in samples from ER-positive breast cancer patients who relapsed after tamoxifen treatment (n=24) compared with samples from patients who did not (n=24). Five genes (TACC1, NOV, PTTG1, BAK1, and TGFB2) were correlated with significantly shorter relapse-free survival (univariate analysis). Finally, we identified TACC1 and a three-gene expression signature (TACC1, NOV, and PTTG1) as independent prognostic markers (multivariate analysis). Aberrant mRNA and protein levels of TACC1, NOV, and PTTG1 were also observed under tamoxifen and/or fulvestrant exposure in resistant CL6.7 cells compared with their respective control MVLN cells. In conclusion, our data identify TACC1, NOV, and PTTG1 as promising new markers that could be used in the clinical management of ER-positive breast cancer patients.

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