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Combining chemotherapy and hormone therapy is a prevalent approach in breast cancer treatment. While the cytotoxic impact of numerous chemotherapy drugs stems from DNA damage, the exact role of these DNA alterations in modulating estrogen receptor α (ERα) machinery remains elusive. The present study aimed to analyze the impact of DNA damage agents on ERα signaling in breast cancer cells and assess the signaling pathways mediating the influence of DNA damage drugs on the ERα machinery. Cell viability was assessed using the MTT method, while the expression of signaling proteins was analyzed by immunoblotting. ERα activity in the cells treated with various drugs (17β-estradiol, tamoxifen, 5-fluorouracil) was assessed through reporter gene assays. In vitro experiments were conducted on MCF7 breast cancer cells subjected to varying durations of 5-fluorouracil (5-FU) treatment. Two distinct cell responses to 5-FU were identified based on the duration of the treatment. A singular dose of 5-FU induces pronounced DNA fragmentation, temporally suppressing ERα signaling while concurrently activating AKT phosphorylation. This suppression reverses upon 5-FU withdrawal, restoring normalcy within ten days. However, chronic 5-FU treatment led to the emergence of 5-FU-resistant cells with irreversible alterations in ERα signaling, resulting in partial hormonal resistance. These changes mirror those observed in cells subjected to UV-induced DNA damage, underscoring the pivotal role of DNA damage in shaping estrogen signaling alterations in breast cancer cells. In summary, the results of the present study suggested that the administration of DNA damage agents to cancer cells can trigger irreversible suppression of estrogen signaling, fostering the development of partial hormonal resistance. This outcome may ultimately impede the efficacy of combined or subsequent chemo- and hormone therapy strategies. [ABSTRACT FROM AUTHOR]

In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast cancer may benefit a patient by allowing for a novel personalized treatment strategy. [ABSTRACT FROM AUTHOR]

Adipocytokines and markers of oxidative stress have been shown to exhibit potential for detection of advanced stage, HER2/neu status and lymph node metastases in patients with breast cancer, as well as in determining the efficiency of anti-cancer treatments. In the present study, blood concentrations of apelin (APLN), retinol-binding protein 4 (RBP4), 8-hydroxydeoxyguanosine (8-oxo-dG) and total antioxidant capacity (TAC) in women with breast cancer with different clinicopathological features were measured prior to and following adjuvant chemotherapy. The study included 60 women with breast cancer stratified according to tumor grade and size, HER-2/neu expression, and lymph node and hormone receptor status. Blood samples were taken before and after two cycles of adjuvant chemotherapy. None of the clinicopathological features were associated with the baseline concentrations of RBP4, 8-oxo-dG or TAC. An increased baseline concentration of APLN was observed in HER-2/neu positive patients. Moreover, through multivariate logistical regression analysis, APLN was shown to be independently associated with a positive HER/neu status. Chemotherapy treatment did not affect the levels of RBP4 or APLN, or TAC values when assessing all the patients, and when assessing the stratified groups of patients. Only 8-oxo-dG was found to be significantly decreased following drug administration (P=0.0009). This preliminary study demonstrated that APLN is a significant and independent predictor of HER-2/neu positive breast cancer. A significant reduction in 8-oxo-dG levels following chemotherapy may indicate its potential clinical utility in monitoring the effects of chemotherapy in breast cancer patients. [ABSTRACT FROM AUTHOR]