Introduction The majority of breast cancers (BCs) are characterized by the expression of estrogen receptor alpha (ERα+). ERα acts as ligand-dependent transcription factor for genes associated with cell survival, proliferation, and tumor growth. Thus, blocking the estrogen agonist effect on ERα is the main strategy in the treatment of ERα+ BCs. However, despite the development of targeted anti-estrogen therapies for ER+ BC, around 30–50% of early breast cancer patients will relapse. Acquired resistance to endocrine therapy is a great challenge in ER+ BC patient treatment. Discussion Anti-estrogen resistance is a consequence of molecular changes, which allow for tumor growth irrespective of estrogen presence. Those changes may be associated with ERα modifications either at the genetic, regulatory or protein level. Additionally, the activation of alternate growth pathways and/or cell survival mechanisms can lead to estrogen-independence and endocrine resistance. Conclusion This comprehensive review summarizes molecular mechanisms associated with resistance to anti-estrogen therapy, focusing on genetic alterations, stress responses, cell survival mechanisms, and cell reprogramming.

Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.

Circulating tumor cell (CTC) numbers in the blood of cancer patients can indicate the progression and invasiveness of tumors, and their prognostic and predictive value has been repeatedly demonstrated. However, the standard baseline CTC count at the beginning of treatment, while informative, is not completely reliable and may not adequately reflect the state of the disease. A growing number of studies indicate that the long-term monitoring of CTC numbers in the same patient provides more comprehensive prognostic data and should be incorporated into clinical practice, as a factor that contributes to therapeutic decisions. This review describes the current status of CTC enumeration as a prognostic and predictive factor, highlights the shortcomings of current solutions, and advocates for longitudinal CTC analysis as a more effective method of the evaluation of developing disease, treatment efficacy, and the long term-monitoring of the minimal residual disease. As evidenced by the described reports, the longitudinal monitoring of CTCs should provide a better and more sensitive prediction of the course of the disease, and its incorporation in clinical practice should be beneficial.

Monitoring of metastatic breast cancer (mBC) is an important issue in the clinical management of patients. Liquid biopsy has become a non-invasive method for detecting and monitoring cancer in body fluids. The presence of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in peripheral blood indicates poor prognosis and may contribute to early detection of progression, but assessment of these levels is still not routine clinical management. The main objective of this study was to estimate the frequency and clinical value of the ESR1 and PIK3CA mutations identified in circulating free DNA (cfDNA.) The second goal was to evaluate whether simultaneous evaluation of CTCs and mutation status in cfDNA increases the prognostic value of liquid biopsy. The results of the analysis of the CTC number and ESR1 and PIK3CA mutations in blood collected from 179 patients with metastatic breast cancer show that ESR1 mutations are more frequent in patients with advanced luminal breast cancer regardless of the type of the treatment. ESR1 mutations appear primarily during progression, as no mutations were found in primary tumor samples. The main conclusion of the study is that combined assessment of CTCs and ESR1 status in liquid biopsy may improve the prognostic value of liquid biopsy.

The majority of the current cancer research is based on two-dimensional cell cultures and animal models. These methods have limitations, including different expressions of key factors involved in carcinogenesis and metastasis, depending on culture conditions. Addressing these differences is crucial in obtaining physiologically relevant models. In this manuscript we analyzed the plasticity of the expression of stem cell and epithelial/mesenchymal markers in breast cancer cells, depending on culture conditions. Significant differences in marker expression were observed in different growth models not only between 2D and 3D conditions but also between two different 3D models. Differences observed in the levels of adherent junction protein E-cadherin in two different 3D models suggest that spatial parameters of cell growth and physical stress in the culture may affect the expression of junction proteins. To provide an explanation of this phenomenon on the grounds of mechanobiology, these parameters were analyzed using a mathematical model of the 3D bioprinted cell culture. The finite element mechanical model generated in this study includes an extracellular matrix and a group of regularly placed cells. The single-cell model comprises an idealized cytoskeleton, cortex, cytoplasm, and nucleus. The analysis of the model revealed that the stress generated by external pressure is transferred between the cells, generating specific stress fields, depending on growth conditions. We have analyzed and compared stress fields in two different growth conditions, each corresponding to a different elasticity of extracellular matrix. We have demonstrated that soft matrix conditions produce more stress than a stiff matrix in the single cell as well as in cellular spheroids. The observed differences can explain the plasticity of E-cadherin expression in response to mechanical stress. These results should contribute to a better understanding of the differences between various growth models.

CTC numbers in the blood of cancer patients can indicate the progression and invasiveness of tumors and their prognostic and predictive value has been repeatedly demonstrated. However, the standard baseline CTC count at the beginning of treatment, while informative, is not completely reliable and may not adequately reflect the state of the disease. The growing number of studies indicate that long-term monitoring of CTC numbers in the same patient provides more comprehensive prognostic data and should be incorporated into clinical practice, as a factor that contributes to therapeutic decisions. This Review describes the current status of CTC enumeration as a prognostic and predictive factor, highlights the shortcomings of current solutions and advocates for longitudinal CTC analysis as a more effective method of the evaluation of developing disease, treatment efficacy, and long term-monitoring of the minimal residual disease.