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Epigenomics Volume 15, 2023 - Issue 18
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Research Article

SIX4, a Potential Therapeutic Target for Estrogen Receptor-Positive Breast Cancer Patients, is Associated with low Promoter Methylation Level

Hua-Tao Wu1 Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China;2 Laboratory for Diagnosis & Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou, 515041, ChinaORCID Iconhttps://orcid.org/0000-0002-1640-6094
ORCID Icon,
Zheng Wu3 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China;4 Department of Physiology/Changjiang Scholar’s Laboratory, Shantou University Medical College, Shantou, 515041, ChinaORCID Iconhttps://orcid.org/0000-0002-1393-7586
ORCID Icon,
Yan-Yu Hou3 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China;4 Department of Physiology/Changjiang Scholar’s Laboratory, Shantou University Medical College, Shantou, 515041, China
,
Ze-Xuan Fang3 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China;4 Department of Physiology/Changjiang Scholar’s Laboratory, Shantou University Medical College, Shantou, 515041, China
,
Bing-Xuan Wu1 Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China;2 Laboratory for Diagnosis & Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
,
Yu Deng1 Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China;2 Laboratory for Diagnosis & Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
,
Yu-Kun Cui2 Laboratory for Diagnosis & Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou, 515041, ChinaCorrespondence[email protected]
&
Jing Liu3 The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China;4 Department of Physiology/Changjiang Scholar’s Laboratory, Shantou University Medical College, Shantou, 515041, ChinaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-7483-4572
ORCID Icon show all
Pages 911-925 | Received 30 Jun 2023, Accepted 10 Oct 2023, Published online: 31 Oct 2023

Figures & data

Figure 1. Expression of SIX4 is high in breast cancer, especially in luminal subtypes.

(A) Expression pattern of SIX4 in different types of malignancies. Dots in the figure represent different samples: red for tumors and green for normal tissue. In different types of malignancies, the cancerous tissues with significantly increased SIX4 are labeled in red and include BRCA, CESC, ESCA, LUAD, LUSC, OV, TGCT, THYM, UCEC and UCS, while malignant tissues with decreased SIX4 are labeled in green and include LAML. (B & C) The increased SIX4 level in breast cancer compared with normal tissues in GEPIA and UALCAN. (D) Expression of SIX4 in different stages of breast cancer. (E) Expression of SIX4 in different molecular subtypes of breast cancer. (F) Expression of SIX4 in different lymph node statuses.

BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; ESCA: Esophageal carcinoma; GEPIA: Gene Expression Profiling Interactive Analysis; LAML: Acute myeloid leukemia; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; OV: Ovarian serous cystadenocarcinoma; TGCT: Testicular germ cell tumor; THYM: Thymoma; UALCAN: University of Alabama at Birmingham Cancer portal; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma.

Figure 1. Expression of SIX4 is high in breast cancer, especially in luminal subtypes. (A) Expression pattern of SIX4 in different types of malignancies. Dots in the figure represent different samples: red for tumors and green for normal tissue. In different types of malignancies, the cancerous tissues with significantly increased SIX4 are labeled in red and include BRCA, CESC, ESCA, LUAD, LUSC, OV, TGCT, THYM, UCEC and UCS, while malignant tissues with decreased SIX4 are labeled in green and include LAML. (B & C) The increased SIX4 level in breast cancer compared with normal tissues in GEPIA and UALCAN. (D) Expression of SIX4 in different stages of breast cancer. (E) Expression of SIX4 in different molecular subtypes of breast cancer. (F) Expression of SIX4 in different lymph node statuses.BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; ESCA: Esophageal carcinoma; GEPIA: Gene Expression Profiling Interactive Analysis; LAML: Acute myeloid leukemia; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; OV: Ovarian serous cystadenocarcinoma; TGCT: Testicular germ cell tumor; THYM: Thymoma; UALCAN: University of Alabama at Birmingham Cancer portal; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma.
Figure 2. Prognostic value of SIX4 level for patients with breast cancer.

(A) Overall survival. (B) Disease-free survival. (C) Relapse-free survival (RFS) in all patients. (D) Luminal A subtype RFS. (E) Luminal B subtype RFS. (F) HER2+ subtype RFS. (G) Basal-like subtype RFS. (H) Normal-like subtype RFS. (I) ER− patient RFS. (J) ER+ patient RFS. (K) PR− patient RFS. (L) PR+ patient RFS. (M) HER2− patient RFS. (N) HER2+ patient RFS. (O) RFS for patients without lymph node metastasis. (P) RFS for patients with lymph node metastasis.

ER: Estrogen receptor; PR: Progesterone receptor.

Figure 2. Prognostic value of SIX4 level for patients with breast cancer. (A) Overall survival. (B) Disease-free survival. (C) Relapse-free survival (RFS) in all patients. (D) Luminal A subtype RFS. (E) Luminal B subtype RFS. (F) HER2+ subtype RFS. (G) Basal-like subtype RFS. (H) Normal-like subtype RFS. (I) ER− patient RFS. (J) ER+ patient RFS. (K) PR− patient RFS. (L) PR+ patient RFS. (M) HER2− patient RFS. (N) HER2+ patient RFS. (O) RFS for patients without lymph node metastasis. (P) RFS for patients with lymph node metastasis.ER: Estrogen receptor; PR: Progesterone receptor.
Figure 3. Mutation of SIX4 in breast cancer.

(A) Mutation percentage and types of SIX4 in breast cancer patients from The Cancer Genome Atlas, PanCancer Atlas. (B) Distribution of SIX4 expression in different copy number variation groups. (C) Correlation of SIX4 mRNA expression with copy number variation groups. (D) Promoter methylation level of SIX4 in primary breast cancer compared with normal breast tissue samples. (E) Promoter methylation level of SIX4 in different molecular subtypes of breast cancer.

Figure 3. Mutation of SIX4 in breast cancer. (A) Mutation percentage and types of SIX4 in breast cancer patients from The Cancer Genome Atlas, PanCancer Atlas. (B) Distribution of SIX4 expression in different copy number variation groups. (C) Correlation of SIX4 mRNA expression with copy number variation groups. (D) Promoter methylation level of SIX4 in primary breast cancer compared with normal breast tissue samples. (E) Promoter methylation level of SIX4 in different molecular subtypes of breast cancer.
Figure 4. Genes associated with SIX4 in breast cancer.

(A) Genes whose expression is correlated with that of SIX4 in breast cancer. (B) Top 50 genes positively correlated with SIX4. (C) Top 50 genes negatively correlated with SIX4. (D)MNAT1. (E)TRMT5. (F)ADNP. (G)SIX1. (H)PPM1A. (I)ARID2. (J)RILP. (K)FXYD5. (L)CLTB. (M)BATF3. (N)CTDNEP1 (DULLARD). (O)CD14.

Figure 4. Genes associated with SIX4 in breast cancer. (A) Genes whose expression is correlated with that of SIX4 in breast cancer. (B) Top 50 genes positively correlated with SIX4. (C) Top 50 genes negatively correlated with SIX4. (D)MNAT1. (E)TRMT5. (F)ADNP. (G)SIX1. (H)PPM1A. (I)ARID2. (J)RILP. (K)FXYD5. (L)CLTB. (M)BATF3. (N)CTDNEP1 (DULLARD). (O)CD14.
Figure 5. Enrichment of gene sets associated with SIX4 in breast cancer.

(A) Double-strand break repair. (B) DNA replication. (C) Microtubule cytoskeleton organization involved in mitosis. (D) Meiotic cell cycle. (E) Cell cycle G2/M phase transition. (F) Humoral immune response. (G) Cell killing. (H) Neutrophil-mediated immunity. (I) Adaptive immune response. (J) IL-1 production.

Figure 5. Enrichment of gene sets associated with SIX4 in breast cancer. (A) Double-strand break repair. (B) DNA replication. (C) Microtubule cytoskeleton organization involved in mitosis. (D) Meiotic cell cycle. (E) Cell cycle G2/M phase transition. (F) Humoral immune response. (G) Cell killing. (H) Neutrophil-mediated immunity. (I) Adaptive immune response. (J) IL-1 production.
Figure 6. Infiltration level of immune cells in breast cancer and different molecular subtypes.
Figure 6. Infiltration level of immune cells in breast cancer and different molecular subtypes.
Figure 7. Prognostic value of SIX4 protein level in breast cancer patients.

(A & B) Representative staining of SIX4 in breast cancer tissues with (A) low and (B) high expression. (C) Protein–protein interactions of SIX4. (D–F) Overall survival of (D) all breast cancer patients, (E) ER− patients and (F) ER+ patients. (G) Staining of SIX4 in the Human Protein Atlas (HPA031794). (H) The protein expression of SIX4 in different malignancies.

ER: Estrogen receptor.

Figure 7. Prognostic value of SIX4 protein level in breast cancer patients. (A & B) Representative staining of SIX4 in breast cancer tissues with (A) low and (B) high expression. (C) Protein–protein interactions of SIX4. (D–F) Overall survival of (D) all breast cancer patients, (E) ER− patients and (F) ER+ patients. (G) Staining of SIX4 in the Human Protein Atlas (HPA031794). (H) The protein expression of SIX4 in different malignancies.ER: Estrogen receptor.

Table 1. The relationship between SIX4 protein level and clinicopathological parameters of breast cancer patients.

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