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WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.

Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS, Wolsky R, Bentolila LA, Grant SG, Elashoff D, Lehr S, Latimer JJ, Bose S, Sattar H, Krum SA, Miranda-Carboni GA - EMBO Mol Med (2013)

Bottom Line: Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation.We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells.Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.

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Triple-negative human breast cancers specifically express high levels of nuclear HMGA2, whose expression has clinical relevance and predicts recurrence-free survival of TNBC patientsDetection of nuclear HMGA2 in human TNBC from different patient groups, as shown by IHC of tissue microarrays. hematoxylin–eosin (H&E) staining from an adjacent section is shown on the left. Arrows indicate enlarged areas shown in insets (40×). Bar, 200 µm.Absence of nuclear HMGA2 expression in other subtypes of human breast cancer (ER+, PR+, HER+, and triple-positive), as analysed by IHC. Bar, 200 µm.Kaplan–Meier survival analysis showing significantly improved recurrence-free survival of Basal-like breast cancer patients with tumours that express lower levels of HMGA2. Patients with higher (red) and lower expression (black) are indicated as well as numbers of patients at risk at specific time points (below each diagram). Hazard ratios (HR) and p values (log rank p) are depicted for each survival analysis. Kaplan–Meier survival data were generated using the publicly accessible online tool KM-plotter.High HMGA2 expression in TNBC is significantly correlated with large tumour size, high proliferation, high nuclear grade and metastasis (HMGA2 expression was determined by IHC in TNBC patient samples and results were correlated with patient data). Associations between markers and clinical parameters that were measured on a continuous or ordinal scale were evaluated using Kendall's Tau coefficient. Associations between markers and binary clinical parameters were tested using an exact trend test, associations with nominal parameters were tested using Fisher's exact test. p Values and patient numbers (n) are indicated in the table. Additional information can be found in Supporting Information Fig S7 and the Materials and Methods Section. p Values of <0.05 were considered to be statistically significant (C, D).Proposed model for WNT10B/β-catenin signalling inducing HMGA2 expression. WNT10B activates canonical Wnt/β-catenin signalling leading to up-regulation of HMGA2 and self-renewal by induction of cell cycle proliferation. ICG-001 disrupts CBP/β-catenin interaction leading to the loss of HMGA2. Black dash arrows and red dash blocking bars represent a possible mechanism of HMGA2 action and/or loss of β-catenin transcriptional activity.
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fig06: Triple-negative human breast cancers specifically express high levels of nuclear HMGA2, whose expression has clinical relevance and predicts recurrence-free survival of TNBC patientsDetection of nuclear HMGA2 in human TNBC from different patient groups, as shown by IHC of tissue microarrays. hematoxylin–eosin (H&E) staining from an adjacent section is shown on the left. Arrows indicate enlarged areas shown in insets (40×). Bar, 200 µm.Absence of nuclear HMGA2 expression in other subtypes of human breast cancer (ER+, PR+, HER+, and triple-positive), as analysed by IHC. Bar, 200 µm.Kaplan–Meier survival analysis showing significantly improved recurrence-free survival of Basal-like breast cancer patients with tumours that express lower levels of HMGA2. Patients with higher (red) and lower expression (black) are indicated as well as numbers of patients at risk at specific time points (below each diagram). Hazard ratios (HR) and p values (log rank p) are depicted for each survival analysis. Kaplan–Meier survival data were generated using the publicly accessible online tool KM-plotter.High HMGA2 expression in TNBC is significantly correlated with large tumour size, high proliferation, high nuclear grade and metastasis (HMGA2 expression was determined by IHC in TNBC patient samples and results were correlated with patient data). Associations between markers and clinical parameters that were measured on a continuous or ordinal scale were evaluated using Kendall's Tau coefficient. Associations between markers and binary clinical parameters were tested using an exact trend test, associations with nominal parameters were tested using Fisher's exact test. p Values and patient numbers (n) are indicated in the table. Additional information can be found in Supporting Information Fig S7 and the Materials and Methods Section. p Values of <0.05 were considered to be statistically significant (C, D).Proposed model for WNT10B/β-catenin signalling inducing HMGA2 expression. WNT10B activates canonical Wnt/β-catenin signalling leading to up-regulation of HMGA2 and self-renewal by induction of cell cycle proliferation. ICG-001 disrupts CBP/β-catenin interaction leading to the loss of HMGA2. Black dash arrows and red dash blocking bars represent a possible mechanism of HMGA2 action and/or loss of β-catenin transcriptional activity.

Mentions: Based on the ability of WNT10B to have clinical significance in TNBC, we hypothesize if HMGA2 would be able to have the same outcome. To this end we conducted IHC analysis for HMGA2 in 14 samples from African-Americans (AA; from The University of Chicago), 31 Caucasian-American samples (from Cedars-Sinai Medical Center) and 14 German samples. There is strong expression of nuclear HMGA2 protein in the TNBC samples (Fig 6A and Supporting Information Fig S6A–C). Furthermore, nuclear HMGA2 expression is restricted to TNBC as it was not detectable in ERα+, PR+, HER2+ and triple positive (TP) breast cancer samples (Fig 6B). More interestingly, HMGA2 expression was not detected at all or at very low levels in four adjacent ‘normal’ breast tissue biopsies, which are from the AA TNBC samples (Supporting Information Fig S6D). We determined the frequency of nuclear HMGA2 expression to be >80% in our TNBC sample set (Supporting Information Fig S6E).


WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.

Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS, Wolsky R, Bentolila LA, Grant SG, Elashoff D, Lehr S, Latimer JJ, Bose S, Sattar H, Krum SA, Miranda-Carboni GA - EMBO Mol Med (2013)

Triple-negative human breast cancers specifically express high levels of nuclear HMGA2, whose expression has clinical relevance and predicts recurrence-free survival of TNBC patientsDetection of nuclear HMGA2 in human TNBC from different patient groups, as shown by IHC of tissue microarrays. hematoxylin–eosin (H&E) staining from an adjacent section is shown on the left. Arrows indicate enlarged areas shown in insets (40×). Bar, 200 µm.Absence of nuclear HMGA2 expression in other subtypes of human breast cancer (ER+, PR+, HER+, and triple-positive), as analysed by IHC. Bar, 200 µm.Kaplan–Meier survival analysis showing significantly improved recurrence-free survival of Basal-like breast cancer patients with tumours that express lower levels of HMGA2. Patients with higher (red) and lower expression (black) are indicated as well as numbers of patients at risk at specific time points (below each diagram). Hazard ratios (HR) and p values (log rank p) are depicted for each survival analysis. Kaplan–Meier survival data were generated using the publicly accessible online tool KM-plotter.High HMGA2 expression in TNBC is significantly correlated with large tumour size, high proliferation, high nuclear grade and metastasis (HMGA2 expression was determined by IHC in TNBC patient samples and results were correlated with patient data). Associations between markers and clinical parameters that were measured on a continuous or ordinal scale were evaluated using Kendall's Tau coefficient. Associations between markers and binary clinical parameters were tested using an exact trend test, associations with nominal parameters were tested using Fisher's exact test. p Values and patient numbers (n) are indicated in the table. Additional information can be found in Supporting Information Fig S7 and the Materials and Methods Section. p Values of <0.05 were considered to be statistically significant (C, D).Proposed model for WNT10B/β-catenin signalling inducing HMGA2 expression. WNT10B activates canonical Wnt/β-catenin signalling leading to up-regulation of HMGA2 and self-renewal by induction of cell cycle proliferation. ICG-001 disrupts CBP/β-catenin interaction leading to the loss of HMGA2. Black dash arrows and red dash blocking bars represent a possible mechanism of HMGA2 action and/or loss of β-catenin transcriptional activity.
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Related In: Results  -  Collection

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fig06: Triple-negative human breast cancers specifically express high levels of nuclear HMGA2, whose expression has clinical relevance and predicts recurrence-free survival of TNBC patientsDetection of nuclear HMGA2 in human TNBC from different patient groups, as shown by IHC of tissue microarrays. hematoxylin–eosin (H&E) staining from an adjacent section is shown on the left. Arrows indicate enlarged areas shown in insets (40×). Bar, 200 µm.Absence of nuclear HMGA2 expression in other subtypes of human breast cancer (ER+, PR+, HER+, and triple-positive), as analysed by IHC. Bar, 200 µm.Kaplan–Meier survival analysis showing significantly improved recurrence-free survival of Basal-like breast cancer patients with tumours that express lower levels of HMGA2. Patients with higher (red) and lower expression (black) are indicated as well as numbers of patients at risk at specific time points (below each diagram). Hazard ratios (HR) and p values (log rank p) are depicted for each survival analysis. Kaplan–Meier survival data were generated using the publicly accessible online tool KM-plotter.High HMGA2 expression in TNBC is significantly correlated with large tumour size, high proliferation, high nuclear grade and metastasis (HMGA2 expression was determined by IHC in TNBC patient samples and results were correlated with patient data). Associations between markers and clinical parameters that were measured on a continuous or ordinal scale were evaluated using Kendall's Tau coefficient. Associations between markers and binary clinical parameters were tested using an exact trend test, associations with nominal parameters were tested using Fisher's exact test. p Values and patient numbers (n) are indicated in the table. Additional information can be found in Supporting Information Fig S7 and the Materials and Methods Section. p Values of <0.05 were considered to be statistically significant (C, D).Proposed model for WNT10B/β-catenin signalling inducing HMGA2 expression. WNT10B activates canonical Wnt/β-catenin signalling leading to up-regulation of HMGA2 and self-renewal by induction of cell cycle proliferation. ICG-001 disrupts CBP/β-catenin interaction leading to the loss of HMGA2. Black dash arrows and red dash blocking bars represent a possible mechanism of HMGA2 action and/or loss of β-catenin transcriptional activity.
Mentions: Based on the ability of WNT10B to have clinical significance in TNBC, we hypothesize if HMGA2 would be able to have the same outcome. To this end we conducted IHC analysis for HMGA2 in 14 samples from African-Americans (AA; from The University of Chicago), 31 Caucasian-American samples (from Cedars-Sinai Medical Center) and 14 German samples. There is strong expression of nuclear HMGA2 protein in the TNBC samples (Fig 6A and Supporting Information Fig S6A–C). Furthermore, nuclear HMGA2 expression is restricted to TNBC as it was not detectable in ERα+, PR+, HER2+ and triple positive (TP) breast cancer samples (Fig 6B). More interestingly, HMGA2 expression was not detected at all or at very low levels in four adjacent ‘normal’ breast tissue biopsies, which are from the AA TNBC samples (Supporting Information Fig S6D). We determined the frequency of nuclear HMGA2 expression to be >80% in our TNBC sample set (Supporting Information Fig S6E).

Bottom Line: Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation.We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells.Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.

Show MeSH
Related in: MedlinePlus