Background: Markers of metabolic coupling have been associated with clinical outcomes in numerous human cancers, including breast cancer. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has been rarely described in phyllodes tumors (PTs) of the breast. Materials and methods: One hundred-one PTs (60 benign, 26 borderline, and 15 malignant) and 9 breast tissues with no pathological lesions were analyzed. Automated immunohistochemical staining for CAV-1, MCT1, and MCT4 was performed using tissue microarray blocks, and their expressions were assessed in both stromal and epithelial components. Results: Compared with normal breast, CAV-1 expression in PTs showed a significant decrease in stromal component (P < 0.001). MCT1 expression was significantly increased in both epithelial and stromal components of PTs compared to normal breast (P < 0.001 and P < 0.001, respectively). Stromal MCT1 and MCT4 expression was different according to the tumor grade of PTs and stromal MCT1 expression tended to increase with increasing tumor grade (P < 0.001). Although not statistically significant, stromal CAV-1 expression tended to decrease with increasing PTs grade. The recurrence rate was higher in the stromal MCT1-positive groups (19.2%, 14/73) than in the stromal MCT1-negative groups (3.9%, 1/28) (P < 0.05). Conclusions: This result suggested that changes of CAV-1, MCT1, and MCT4 may be associated with tumorigenesis and progression of PTs of the breast. Keywords Phyllodes tumor, CAV-1, MCT 1, MCT4, Metabolic coupling. Citation Format: Ji Shin Leee, Nah Ihm Kim, Min Ho Park. Metabolic coupling in phyllodes tumor of the breast and its correlation to tumor progression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-09-06.
Background: Human epididymis protein 4 (HE4), also known as WFDC2, is a member of whey acidic protein (WAP) family with a presumptive role in natural immunity. HE4 expression has been increased in many cancer types, particularly in gynecologic and pulmonary cancers. HE4 has been identified as an important serum biomarker in the diagnosis and monitoring of epithelial ovarian cancer. Recent researches have demonstrated that HE4 levels in serum and tissues are elevated in patients with breast cancer and HE4 is thought be involved in breast cancer progression. In contrast, expression of HE4 in ductal carcinoma in situ (DCIS) has not been well characterized yet. The present work was undertaken to evaluate serum and tissue levels of HE4 in DCIS and their correlations with clinicopathological features of DCIS. Materials and methods: Preoperative serum HE4 levels in 59 DCIS patients was analyzed using the ARCHITECT assay. Tissue microarray containing DCIS and adjacent normal tissues from the same cohort were tested for HE4 mRNA and protein by RNAscope in situ hybridization (ISH) and immunohistochemistry analysis, respectively. Tissue microarray containing only DCS tissues from 41 patients were also tested for HE4 mRNA and protein. To validate prognostic potential of HE4 in breast cancer patients, the BreastMark database was used. Results: HE4 levels in 59 DCIS patients ranged from 23.5 to 86.3 pmol/L (mean ± SD: 39.4 ± 11.9). Based on the cutoff level, there were no abnormal cases for HE4. Serum HE4 levels did not differ according to clinicopathological parameters except for menopause status. RNAscope ISH and immunohistochemistry confirmed an increase in HE4 in DCIS tissues compared with their corresponding normal tissues. Spearman’s correlation analyses revealed no significant correlation between serum and tissue levels of HE4. Among 100 DCIS tissues, there was a positive correlation between HE4 mRNA ISH scores and HE4 immunohistochemical staining scores (r = 0.771, P < 0.001). High mRNA and protein expression of HE4 were observed in 25 of 99 (25.3%) and 34 of 99 (34.3%) cases, respectively. High mRNA HE4 expression was significantly associated with low stromal tumor infiltrating lymphocyte (TIL) density scores, ER positivity, HER2 negativity, and HR+/HER2- subtype. High protein HE4 expression was also significantly associated with absence of comedo-type necrosis, low stromal TIL density scores, ER positivity, HER2 negativity, and HR+/HER2- subtype. HE4 mRNA and protein expression did not correlate with recurrence of DCIS. In breast cancer patients, high HE4 expression was significantly associated with good survival in the overall group (HR = 0.838, P = 0.003, n = 2,652) and lymph node negative group (HR = 0.791, P = 0.029, n = 1,183). Conclusions: Our study revealed that serum HE4 is not elevated in patients with DCIS. High expression of HE4 mRNA and protein in DCIS tissues are associated with good clinicopathological characteristics, which warrant. further investigations. Citation Format: Ji Shin Leee, Nah Ihm Kim, Min Ho Park. Evaluation of human epididymis protein 4 serum and tissue expression in ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-22.
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