Ongoing research continues to elucidate the complex role of ephrin receptors (EPHs) and their ligands (ephrins) in breast cancer pathogenesis, with their varying expression patterns implied to have an important impact on patients’ outcome. The current study aims to investigate the clinical significance of EPHA2, EPHA4, and EPHA7 expression in triple-negative breast cancer (TNBC) cases. EPHA2, EPHA4, and EPHA7 protein expression was assessed immunohistochemically on formalin-fixed and paraffin-embedded (FFPE) TNBC tissue sections from 52 TNBC patients and correlated with key clinicopathologic parameters and patients’ survival data (overall survival (OS); disease-free survival (DFS)). EPHA2, EPHA4, and EPHA7 expression was further examined in TNBC cell lines. EPHA2 overexpression was observed in 26 (50%) of the TNBC cases, who exhibited a shorter OS and DFS than their low-expression counterparts, with EPHA2 representing an independent prognostic factor for OS and DFS (p = 0.0041 and p = 0.0232, respectively). EPHA4 overexpression was associated with lymph node metastasis in TNBC patients (p = 0.0546). Alterations in EPHA2, EPHA4, and EPHA7 expression levels were also noted in the examined TNBC cell lines. Our study stresses that EPHA2 expression constitutes a potential prognostic factor for TNBC patients. Given the limited treatment options and poorer outcome that accompany the TNBC subtype, EPHA2 could also pose as a target for novel, more personalized, and effective therapeutic approaches for those patients.

Background and Objectives: Calcium (Ca²⁺) signaling is critical for the normal functioning of various cellular activities. However, abnormal changes in cellular Ca²⁺ can contribute to pathological conditions, including various types of cancer. The maintenance of intracellular Ca²⁺ levels is achieved through tightly regulated processes that help maintain Ca²⁺ homeostasis. Several types of regulatory proteins are involved in controlling intracellular Ca²⁺ levels, including the sarco/endoplasmic reticulum (SR/ER) Ca²⁺ ATPase pump (SERCA), which maintains Ca²⁺ levels released from the SR/ER. In total, three ATPase SR/ER Ca²⁺-transporting (ATP2A) 1-3 genes exist, which encode for several isoforms whose expression profiles are tissue-specific. Recently, it has become clear that abnormal SERCA expression and activity are associated with various types of cancer, including breast cancer. Breast carcinomas represent 40% of all cancer types that affect women, with a wide variety of pathological and clinical conditions. Materials and methods: Using cBioPortal breast cancer patient data, Kaplan–Meier plots demonstrated that high ATP2A1 and ATP2A3 expression was associated with reduced patient survival. Results: The present study found significantly different SERCA specific-type expressions in a series of breast cancer cell lines. Moreover, bioinformatics analysis indicated that ATP2A1 and ATP2A3 expression was highly altered in patients with breast cancer. Conclusion: Overall, the present data suggest that SERCA gene-specific expressioncan possibly be considered as a crucial target for the control of breast cancer development and progression.

Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells’ proliferative capacity, and overall disease-free patients’ survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells’ proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients’ survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients’ survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

Breast cancer is one of the most lethal malignancies in women worldwide and is characterized by rapid growth and low survival rates, despite advances in tumor biology and therapies. Novel therapeutic approaches require new insights into the molecular mechanisms of malignant transformation and progression. To this end, here, we identified Prox1 as a negative regulator of proliferation and tumor-related metabolism in breast cancer. In particular, we showed that breast tumors from human patients exhibited reduced levels of Prox1 expression, while high expression levels of Prox1 were associated with a favorable prognosis in breast cancer patients. Moreover, we experimentally demonstrated that Prox1 was sufficient to strongly suppress proliferation, migration, and the Warburg effect in human breast cancer cells without inducing apoptosis. Most importantly, over-expression of Prox1 inhibited breast tumor growth in vivo in both heterotopic and orthotopic xenograft mouse models. The anti-tumorigenic effect of Prox1 was mediated by the direct repression of c-Myc transcription and its downstream target genes. Consistently, c-Myc over-expression from an artificial promoter that was not targeted by Prox1 reversed Prox1’s anti-tumor effects. These findings suggest that Prox1 has a tumor suppressive role via direct transcriptional regulation of c-Myc, making it a promising therapeutic gene for breast cancer.