Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Abstract

Purpose:
Carbonic anhydrase IX (CAIX) is a well-established prognostic marker in breast cancer (BC). Nevertheless, this prognostic value is yet to be confirmed in BC subtypes. This study aims to investigate the prognostic effects of CAIX in oestrogen receptor (ER)-negative (ER−) BCs and to establish pathways related to cytoplasmic CAIX expression in ER− and lymph node-negative BCs.

Methods:
Immunohistochemistry was performed to identify the prognostic role of CAIX protein expression in ER− tissue microarrays (TMAs) (n = 191). CAIX-positive samples (n = 37) were transcriptionally profiled by TempO-Seq and analysed by STRING. Real-time quantitative PCR (RT-qPCR) analysis was used to validate differentially expressed genes.

Results:
Overexpression of cytoplasmic CAIX was an independent predictor of recurrence free survival, disease-free survival and overall survival in ER− cohort. RNA transcriptomic analysis identified 10 significant genes in ER− cohort and 3 genes in the node-negative group. The STRING database demonstrated a significant interaction between MUCL1 and GALNT6, which were linked with extracellular matrix organisation, degradation of the extracellular matrix and disease of glycosylation pathways. In the node-negative group, SPNS2 is mainly involved in the sphingolipid de novo biosynthesis pathway. A significant correlation between cytoplasmic SphK1 and cytoplasmic hypoxia-inducible factor-1α was observed. Among the 10 genes, 7 genes (SERHL2, GALNT6, MUCL1, MMP7, PITX2, CEACAM6 and SPNS2) were selected, and their expression was quantitatively assessed by RT-qPCR. The PCR data of these genes showed that SERHL2, GALNT6, MUCL1, PITX2, and SPNS2 mRNA levels were expressed in MDA-MB-231 BC cell lines at variable levels of hypoxic exposure.

Conclusion:
Cytoplasmic CAIX was independently associated with poor prognosis in ER− BC. Gene expression profiles shed light on the pathways and genes associated with hypoxia in ER− BC. In node-negative patients, SPNS2 was of particular interest.

People
Shamis, Suad Ahmad Khalifa
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Shamis, Suad Ahmad Khalifa and Savioli, Francesca and Ammar, Aula and Al-Badran, Sara S.F. and Hatthakarnkul, Phimmada and Leslie, Holly and Mallon, Elizabeth and Jamieson, Nigel B. and McMillan, Donald C. and Edwards, Joanne (2024) Spatial transcriptomic analysis of tumour with high and low CAIX expression in TNBC tissue samples using GeoMx™ RNA assay. Histology and Histopathology: Cellular and Molecular Biology, 39. pp. 177-200. ISSN 0213-3911

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Quinn, Jean A.
Author

Pennel, Kathryn and Kurniawan, Ahmad and Al-Badran, Sara Samir Foad and Schubert Santana, Leonor and Quinn, Jean and Nixon, Colin and Hatthakarnkul, Phimmada and Maka, Noori and Roxburgh, Campbell and McMillan, Donald and Edwards, Joanne (2024) IL6 and IL6R as prognostic biomarkers in colorectal cancer. Biomolecules, 14 (12): 1629. ISSN 2218-273X

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Galbraith, Norman J. and Quinn, Jean A. and Al-Badran, Sara Sf and Pennel, Kathryn A.F. and Hillson, Lily V.S. and Hatthakarnkul, Phimmada and McKenzie, Molly and Maka, Noori and Loi, Lynette and Frixou, Mikaela and Steele, Colin W. and Roxburgh, Campbell S. and Horgan, Paul G. and McMillan, Donald C. and Edwards, Joanne (2024) TAK1 expression is associated with increased PD-L1 and decreased cancer-specific survival in microsatellite-stable colorectal cancer. Translational Oncology, 48: 102064. ISSN 1944-7124

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Al-Badran, Sara S.F.
Author

Pennel, Kathryn and Kurniawan, Ahmad and Al-Badran, Sara Samir Foad and Schubert Santana, Leonor and Quinn, Jean and Nixon, Colin and Hatthakarnkul, Phimmada and Maka, Noori and Roxburgh, Campbell and McMillan, Donald and Edwards, Joanne (2024) IL6 and IL6R as prognostic biomarkers in colorectal cancer. Biomolecules, 14 (12): 1629. ISSN 2218-273X

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Galbraith, Norman J. and Quinn, Jean A. and Al-Badran, Sara Sf and Pennel, Kathryn A.F. and Hillson, Lily V.S. and Hatthakarnkul, Phimmada and McKenzie, Molly and Maka, Noori and Loi, Lynette and Frixou, Mikaela and Steele, Colin W. and Roxburgh, Campbell S. and Horgan, Paul G. and McMillan, Donald C. and Edwards, Joanne (2024) TAK1 expression is associated with increased PD-L1 and decreased cancer-specific survival in microsatellite-stable colorectal cancer. Translational Oncology, 48: 102064. ISSN 1944-7124

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McKenzie, Molly
Author

Dolan, Ross D. and Pennel, Kathryn and Thompson, Joshua and McKenzie, Molly and Alexander, Peter and Richards, Colin and Black, Douglas and Abbass, Tanvir and Maka, Noori and McGovern, Josh and Roseweir, Antonia and McSorley, Stephen T. and Horgan, Paul G. and Roxburgh, Campbell and McMillan, Donald C. and Edwards, Joanne (2025) The relationship between tumour necrosis, systemic inflammation, body composition and survival in patients with colon cancer. BJC Reports, 3 (1): 7. ISSN 2731-9377

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Galbraith, Norman J. and Quinn, Jean A. and Al-Badran, Sara Sf and Pennel, Kathryn A.F. and Hillson, Lily V.S. and Hatthakarnkul, Phimmada and McKenzie, Molly and Maka, Noori and Loi, Lynette and Frixou, Mikaela and Steele, Colin W. and Roxburgh, Campbell S. and Horgan, Paul G. and McMillan, Donald C. and Edwards, Joanne (2024) TAK1 expression is associated with increased PD-L1 and decreased cancer-specific survival in microsatellite-stable colorectal cancer. Translational Oncology, 48: 102064. ISSN 1944-7124

See full publications list
Hatthakarnkul, Phimmada
Author

Pennel, Kathryn and Kurniawan, Ahmad and Al-Badran, Sara Samir Foad and Schubert Santana, Leonor and Quinn, Jean and Nixon, Colin and Hatthakarnkul, Phimmada and Maka, Noori and Roxburgh, Campbell and McMillan, Donald and Edwards, Joanne (2024) IL6 and IL6R as prognostic biomarkers in colorectal cancer. Biomolecules, 14 (12): 1629. ISSN 2218-273X

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Galbraith, Norman J. and Quinn, Jean A. and Al-Badran, Sara Sf and Pennel, Kathryn A.F. and Hillson, Lily V.S. and Hatthakarnkul, Phimmada and McKenzie, Molly and Maka, Noori and Loi, Lynette and Frixou, Mikaela and Steele, Colin W. and Roxburgh, Campbell S. and Horgan, Paul G. and McMillan, Donald C. and Edwards, Joanne (2024) TAK1 expression is associated with increased PD-L1 and decreased cancer-specific survival in microsatellite-stable colorectal cancer. Translational Oncology, 48: 102064. ISSN 1944-7124

See full publications list
Lynch, Gerard
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

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Lian, Guang-Yu
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

McKenzie, Molly and Lian, Guang-Yu and Pennel, Kathryn A.F. and Quinn, Jean A. and Jamieson, Nigel B. and Edwards, Joanne (2024) NFκB signalling in colorectal cancer: examining the central dogma of IKKα and IKKβ signalling. Heliyon, 10 (12): e32904. ISSN 2405-8440

Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966

See full publications list
Numprasit, Warapan
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

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Romics Jr, Laszlo
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

See full publications list
Andersen, Ditte
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Hatthakarnkul, Phimmada and Pennel, Kathryn and Alexander, Peter and Van Wyk, Hester and Roseweir, Antonia and Inthagard, Jitwadee and Hay, Jennifer and Andersen, Ditte and Maka, Noori and Park, James and Roxburgh, Campbell and Thuwajit, Chanitra and McMillan, Donald and Edwards, Joanne (2024) Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer. Journal of Pathology: Clinical Research, 10 (3): e12374. ISSN 2056-4538

Pennel, Kathryn A.F. and Hatthakarnkul, Phimmada and Wood, Colin S. and Lian, Guang-Yu and Al-Badran, Sara and Quinn, Jean A. and Legrini, Assya and Inthagard, Jitwadee and Alexander, Peter G. and van Wyk, Hester and Kurniawan, Ahmad and Hashmi, Umar and Gillespie, Michael A. and Mills, Megan and Ammar, Aula and Hay, Jennifer and Andersen, Ditte and Nixon, Colin and Rebus, Selma and Chang, David K. and Kelly, Caroline and Harkin, Andrea and Graham, Janet and Church, David and Tomlinson, Ian and Saunders, Mark and Iveson, Tim and Lannagan, Tamsin R. M. and Jackstadt, Rene and Maka, Noori and Horgan, Paul G. and Roxburgh, Campbell S. D. and Sansom, Owen J. and McMillan, Donald C. and Steele, Colin W. and Jamieson, Nigel B. and Park, James H. and Roseweir, Antonia K. and Edwards, Joanne (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43: 64. ISSN 1756-9966

See full publications list
Mallon, Elizabeth
Author

Shamis, Suad A.K. and Quinn, Jean and Al-Badran, Sara and McKenzie, Molly and Hatthakarnkul, Phimmada and Lynch, Gerard and Lian, Guang-Yu and Numprasit, Warapan and Romics Jr, Laszlo and Andersen, Ditte and Mallon, Elizabeth and McMillan, Donald C. and Edwards, Joanne (2024) Elucidation of dysregulated pathways associated with hypoxia in oestrogen receptor-negative breast cancer. Cancer Medicine, 13 (23): e70274. ISSN 2045-7634

Shamis, Suad Ahmad Khalifa and Savioli, Francesca and Ammar, Aula and Al-Badran, Sara S.F. and Hatthakarnkul, Phimmada and Leslie, Holly and Mallon, Elizabeth and Jamieson, Nigel B. and McMillan, Donald C. and Edwards, Joanne (2024) Spatial transcriptomic analysis of tumour with high and low CAIX expression in TNBC tissue samples using GeoMx™ RNA assay. Histology and Histopathology: Cellular and Molecular Biology, 39. pp. 177-200. ISSN 0213-3911

See full publications list
McMillan, D.C.
Author

Bradley, Nicholas A. and Walter, Amy and Sankey, Chiara and Wilson, Alasdair and Siddiqui, Tamim and Roxburgh, Campbell D. and McMillan, Donald C. and Guthrie, Graeme J.K. (2025) Longitudinal association between statins and changes in CT derived body composition in patients with abdominal aortic aneurysm. Journal of Cachexia, Sarcopenia and Muscle, 16 (2). ISSN 2190-5991

Thompson, Joshua J. and MacLeod, Nicholas and Will, Sarah and O'Rourke, Fraser and McGovern, Josh and Roxburgh, Campbell and Edwards, Joanne and Dolan, Ross D. and McMillan, Donald C. (2025) The prognostic value of a laboratory cachexia score (LCAS) defined by LDH, CRP and albumin in patients with advanced lung cancer. BMC Cancer, 25: 543. ISSN 1471-2407

Dolan, Ross D. and Pennel, Kathryn and Thompson, Joshua and McKenzie, Molly and Alexander, Peter and Richards, Colin and Black, Douglas and Abbass, Tanvir and Maka, Noori and McGovern, Josh and Roseweir, Antonia and McSorley, Stephen T. and Horgan, Paul G. and Roxburgh, Campbell and McMillan, Donald C. and Edwards, Joanne (2025) The relationship between tumour necrosis, systemic inflammation, body composition and survival in patients with colon cancer. BJC Reports, 3 (1): 7. ISSN 2731-9377

See full publications list
Edwards, J.
Author

Thompson, Joshua J. and MacLeod, Nicholas and Will, Sarah and O'Rourke, Fraser and McGovern, Josh and Roxburgh, Campbell and Edwards, Joanne and Dolan, Ross D. and McMillan, Donald C. (2025) The prognostic value of a laboratory cachexia score (LCAS) defined by LDH, CRP and albumin in patients with advanced lung cancer. BMC Cancer, 25: 543. ISSN 1471-2407

Dolan, Ross D. and Pennel, Kathryn and Thompson, Joshua and McKenzie, Molly and Alexander, Peter and Richards, Colin and Black, Douglas and Abbass, Tanvir and Maka, Noori and McGovern, Josh and Roseweir, Antonia and McSorley, Stephen T. and Horgan, Paul G. and Roxburgh, Campbell and McMillan, Donald C. and Edwards, Joanne (2025) The relationship between tumour necrosis, systemic inflammation, body composition and survival in patients with colon cancer. BJC Reports, 3 (1): 7. ISSN 2731-9377

Pennel, Kathryn and Kurniawan, Ahmad and Al-Badran, Sara Samir Foad and Schubert Santana, Leonor and Quinn, Jean and Nixon, Colin and Hatthakarnkul, Phimmada and Maka, Noori and Roxburgh, Campbell and McMillan, Donald and Edwards, Joanne (2024) IL6 and IL6R as prognostic biomarkers in colorectal cancer. Biomolecules, 14 (12): 1629. ISSN 2218-273X

See full publications list
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