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Andrew R. Green - One of the best experts on this subject based on the ideXlab platform.

  • Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer.
    International journal of molecular sciences, 2020
    Co-Authors: Lutfi Alfarsi, Rokaya El-ansari, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • co expression effect of SLC7A5 slc3a2 to predict response to endocrine therapy in oestrogen receptor positive breast cancer
    International Journal of Molecular Sciences, 2020
    Co-Authors: Lutfi Alfarsi, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Rokaya Elansari, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer
    British journal of cancer, 2019
    Co-Authors: Rokaya El Ansari, Madeleine L. Craze, Lutfi Alfarsi, Emad A. Rakha, Ian O Ellis, Maryam Althobiti, Andrew R. Green
    Abstract:

    Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome. SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells. High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p 

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Purpose Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort ( n  = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome ( p  

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p 

Harley T. Kurata - One of the best experts on this subject based on the ideXlab platform.

  • Control of SLC7A5 sensitivity by the voltage-sensing domain of Kv1 channels.
    eLife, 2020
    Co-Authors: Shawn M. Lamothe, Nazlee Sharmin, Grace Silver, Motoyasu Satou, Yubin Hao, Toru Tateno, Victoria A. Baronas, Harley T. Kurata
    Abstract:

    Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter SLC7A5. In this study, we report that Kv1.1 channels are also regulated by SLC7A5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement ('disinhibition') with holding potentials more negative than -120 mV. Knockdown of endogenous SLC7A5 leads to larger Kv1.1 currents and strongly attenuates the disinhibition effect, suggesting that SLC7A5 regulation of Kv1.1 involves channel inhibition that can be reversed by supraphysiological hyperpolarizing voltages. We investigated chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to SLC7A5, and localize a specific position in S1 with prominent effects on SLC7A5 sensitivity. Overall, our study highlights multiple SLC7A5-sensitive Kv1 subunits, and identifies the voltage-sensing domain as a determinant of SLC7A5 modulation of Kv1 channels.

  • SLC7A5 alters Kvβ-mediated regulation of Kv1.2.
    The Journal of general physiology, 2020
    Co-Authors: Shawn M. Lamothe, Harley T. Kurata
    Abstract:

    The voltage-gated potassium channel Kv1.2 plays a pivotal role in neuronal excitability and is regulated by a variety of known and unknown extrinsic factors. The canonical accessory subunit of Kv1.2, Kvβ, promotes N-type inactivation and cell surface expression of the channel. We recently reported that a neutral amino acid transporter, SLC7A5, alters the function and expression of Kv1.2. In the current study, we investigated the effects of SLC7A5 on Kv1.2 in the presence of Kvβ1.2 subunits. We observed that SLC7A5-induced suppression of Kv1.2 current and protein expression was attenuated with cotransfection of Kvβ1.2. However, gating effects mediated by SLC7A5, including disinhibition and a hyperpolarizing shift in channel activation, were observed together with Kvβ-mediated inactivation, indicating convergent regulation of Kv1.2 by both regulatory proteins. SLC7A5 influenced several properties of Kvβ-induced inactivation of Kv1.2, including accelerated inactivation, a hyperpolarizing shift and greater extent of steady-state inactivation, and delayed recovery from inactivation. These modified inactivation properties were also apparent in altered deactivation of the Kv1.2/Kvβ/SLC7A5 channel complex. Taken together, these findings illustrate a functional interaction arising from simultaneous regulation of Kv1.2 by Kvβ and SLC7A5, leading to powerful effects on Kv1.2 expression, gating, and overall channel function.

  • Control of SLC7A5 sensitivity by the voltage-sensing domain of Kv1 channels
    2020
    Co-Authors: Nazlee Sharmin, Shawn M. Lamothe, Grace Silver, Yubin Hao, Victoria A. Baronas, Harley T. Kurata
    Abstract:

    Many voltage-dependent ion channels are regulated by accessory proteins, although the underlying mechanisms and consequences are often poorly understood. We recently reported a novel function of the amino acid transporter SLC7A5 as a powerful regulator of Kv1.2 voltage-dependent activation. In this study, we report that Kv1.1 channels are also regulated by SLC7A5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement (9disinhibition9) with holding potentials more negative than -120 mV. Disinhibition of Kv1.1 is strongly attenuated by shRNA knockdown of endogenous SLC7A5. We investigated a variety of chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to SLC7A5. Overall, our study highlights additional SLC7A5-sensitive Kv1 subunits, and demonstrates that features of SLC7A5 sensitivity can be swapped by exchanging voltage-sensing domains.

  • SLC7A5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations.
    Nature communications, 2018
    Co-Authors: Victoria A. Baronas, Runying Y. Yang, Luis Carlos Morales, Simonetta Sipione, Harley T. Kurata
    Abstract:

    Kv1.2 is a prominent voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. We explored multi-protein complexes containing Kv1.2 using mass spectrometry followed by screening for effects on Kv1.2. We report that SLC7A5, a neutral amino acid transporter, has a profound impact on Kv1.2. Co-expression with SLC7A5 reduces total Kv1.2 protein, and dramatically hyperpolarizes the voltage-dependence of activation by −47 mV. These effects are attenuated by expression of Slc3a2, a known binding partner of SLC7A5. The profound SLC7A5-mediated current suppression is partly explained by a combination of gating effects including accelerated inactivation and a hyperpolarizing shift of channel activation, causing channels to accumulate in a non-conducting state. Two recently reported SLC7A5 mutations linked to neurodevelopmental delay exhibit a localization defect and have attenuated effects on Kv1.2. In addition, epilepsy-linked gain-of-function Kv1.2 mutants exhibit enhanced sensitivity to SLC7A5. Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that SLC7A5, a neutral amino acid transporter, has a profound impact on Kv1.2.

Emad A. Rakha - One of the best experts on this subject based on the ideXlab platform.

  • Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer.
    International journal of molecular sciences, 2020
    Co-Authors: Lutfi Alfarsi, Rokaya El-ansari, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • co expression effect of SLC7A5 slc3a2 to predict response to endocrine therapy in oestrogen receptor positive breast cancer
    International Journal of Molecular Sciences, 2020
    Co-Authors: Lutfi Alfarsi, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Rokaya Elansari, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer
    British journal of cancer, 2019
    Co-Authors: Rokaya El Ansari, Madeleine L. Craze, Lutfi Alfarsi, Emad A. Rakha, Ian O Ellis, Maryam Althobiti, Andrew R. Green
    Abstract:

    Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome. SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells. High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p 

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Purpose Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort ( n  = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome ( p  

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p 

Ian O Ellis - One of the best experts on this subject based on the ideXlab platform.

  • Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer.
    International journal of molecular sciences, 2020
    Co-Authors: Lutfi Alfarsi, Rokaya El-ansari, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • co expression effect of SLC7A5 slc3a2 to predict response to endocrine therapy in oestrogen receptor positive breast cancer
    International Journal of Molecular Sciences, 2020
    Co-Authors: Lutfi Alfarsi, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Rokaya Elansari, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer
    British journal of cancer, 2019
    Co-Authors: Rokaya El Ansari, Madeleine L. Craze, Lutfi Alfarsi, Emad A. Rakha, Ian O Ellis, Maryam Althobiti, Andrew R. Green
    Abstract:

    Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome. SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells. High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p 

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Purpose Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort ( n  = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome ( p  

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p 

Madeleine L. Craze - One of the best experts on this subject based on the ideXlab platform.

  • Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer.
    International journal of molecular sciences, 2020
    Co-Authors: Lutfi Alfarsi, Rokaya El-ansari, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • co expression effect of SLC7A5 slc3a2 to predict response to endocrine therapy in oestrogen receptor positive breast cancer
    International Journal of Molecular Sciences, 2020
    Co-Authors: Lutfi Alfarsi, Madeleine L. Craze, Emad A. Rakha, Ian O Ellis, Brendah K. Masisi, Omar J. Mohammed, Rokaya Elansari, Andrew R. Green
    Abstract:

    The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

  • Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer
    British journal of cancer, 2019
    Co-Authors: Rokaya El Ansari, Madeleine L. Craze, Lutfi Alfarsi, Emad A. Rakha, Ian O Ellis, Maryam Althobiti, Andrew R. Green
    Abstract:

    Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome. SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells. High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p 

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Purpose Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort ( n  = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome ( p  

  • The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Rokaya El-ansari, Madeleine L. Craze, Lutfi Alfarsi, Daniele Soria, Maria Diez-rodriguez, Christopher C. Nolan, Emad A. Rakha, Ian O Ellis, Andrew R. Green
    Abstract:

    Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5−/SLC7A5−/SLC3A2−), high SLC1A5 (SLC1A5+/SLC7A5−/SLC3A2−), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p