Lorena Cayetano-Salazar

El cáncer de mama es una de las principales causas de muertepor cáncer en mujeres y su progresión depende, entreotros factores, de procesos celulares asociados a la migracióne invasión. La familia de proteínas ezrina-radixina-moesina(ERM) participa en la reorganización del citoesqueleto y lamotilidad celular; en particular, ezrina se ha implicado en etapasclave de progresión tumoral y metástasis. Por otro lado,estudios epidemiológicos y experimentales sugieren unarelación entre obesidad y progresión del cáncer de mama,en la que leptina, una hormona secretada por adipocitos,puede favorecer fenotipos más agresivos al incrementarla migración e invasión. Sin embargo, el vínculo funcionalentre leptina y ezrina no se ha explorado por completo. Elobjetivo de este estudio fue evaluar si el silenciamiento deezrina inhibe la migración e invasión inducidas por leptina encélulas de cáncer de mama. Observamos que la exposición aleptina incrementó la migración e invasión en las líneas celularesMDA-MB-231 y MCF-7. En contraste, el silenciamientode ezrina mediante RNA de interferencia (siRNA) redujosignificativamente la migración e invasión en ambas líneascelulares, tanto en condiciones basales como en presenciade leptina. En conjunto, estos resultados apoyan que ezrinaparticipa funcionalmente en la motilidad e invasividad decélulas de cáncer de mama y sugieren su potencial comoblanco terapéutico para limitar procesos asociados con progresióntumoral.

Background/Objectives: Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. Methods: The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. Results:TIMP1 was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. TIMP2, TIMP3, and TIMP4 were downregulated in tumors. High expression of TIMP1 and TIMP4 correlated with better overall survival. TIMP1-associated genes were enriched in NF-kappa and PI3K–Akt signaling and actin cytoskeleton components. TIMP2 was linked to Hedgehog and MAPK pathways and actin-related elements. TIMP3 correlated with Hedgehog and PI3K–Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K–Akt, DNA damage pathways, and actin organization. TIMP2 showed strong positive correlations with MMP2 and MMP14, while TIMP4 showed negative correlations with MMP1 and MMP9. Interestingly, we found a strong positive correlation between TIMP2 and TIMP3 with ADAM12, as well as between TIMP2 and TIMP3 with ADAM10, and negative correlations with ADAM15. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. Conclusions: TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. TIMP1 emerges as the only consistently overexpressed inhibitor, while TIMP4 appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors.

El cáncer de mama es la principal causa de muerte en mujeres a nivel mundial. REST es considerado un regulador clave en la progresión del cáncer de mama. La pérdida de su función se asocia con un fenotipo más agresivo, mayor riesgo de recaída y peor pronóstico de las pacientes. Sin embargo, el papel de REST en cáncer de mama es aún incierto, ya que se ha visto puede favorecer o inhibir la progresión del cáncer de mama. Mediante un enfoque bioinformático a partir del conjunto de datos TCGA, GEPIA 2, cBioPortal y THPA, se evaluó la expresión del transcrito y proteína de REST en pacientes con cáncer de mama y en los diferentes subtipos de esta patología, se evaluó la correlación en la expresión de REST y de los de marcadores moleculares ER, PR, HER2 y Ki67 y se analizó la supervivencia global de las pacientes con diferencias en la expresión de REST. Se encontró que la expresión de REST es mayor y con localización nuclear en tejido tumoral mamario comparado con tejido normal. De acuerdo con la clasificación TNM, la expresión de REST no mostró cambios significativos. En cambio, en la clasificación molecular, el subtipo luminal B presenta una mayor expresión de REST comparado con el resto de los subtipos y la expresión de REST se correlaciona con la expresión de los marcadores moleculares ER, PR, HER2 y Ki67. Finalmente, se encontró una menor supervivencia general en las pacientes con subtipo HER2 que muestran mayor expresión de REST.

Tissue inhibitors of metalloproteinases (TIMPs) are essential players during tumor progression in various types of cancer, including breast cancer. TIMPs regulate the activity of matrix metallo-proteinases (MMPs) at different levels. However, a dual role for TIMPs in breast carcinogenesis, either promoting or inhibiting tumor progression, has been observed. By a comprehensive bioin-formatics analysis using different databases, we report that of the four TIMPs, only TIMP-1 is overexpressed in tumor breast tissue. However, TIMP-2, TIMP-3, and especially TIMP-4 present lower levels in breast tumor tissue than in normal tissue. Interestingly, high levels of TIMP-1 are associated with shorter survival in breast cancer patients. In contrast, low TIMP-2, TIMP-3, and TIMP-4 levels are associated with poor survival. Function enrichment analysis showed that TIMP-3 has the highest interactions with its target proteins and a higher number of processes re-lated to mammary carcinogenesis. We found differential expression of TIMP-1 concerning TIMP-3 and TIMP-4 in breast cancer and normal tissue. TIMP-4 has a significant relationship with cancer staging, including tumor size, lymph node spread, and metastasis. The correlation between immune cell infiltrates and TIMP expression is of great importance as they provide in-formation on breast cancer diagnosis, prognosis, progression, and response to treatment.

Cancer is a public health problem worldwide, and one of the crucial steps within tumor progression is the invasion and metastasis of cancer cells, which are directly related to cancer‐associated deaths in patients. Recognizing the molecular markers involved in invasion and metastasis is essential to find targeted therapies in cancer. Interestingly, about 50% of the discovered drugs used in chemotherapy have been obtained from natural sources such as plants, including isoflavonoids. Until now, most drugs are used in chemotherapy targeting proliferation and apoptosis‐related molecules. Here, we review recent studies about the effect of isoflavonoids on molecular targets and signaling pathways related to invasion and metastasis in cancer cell cultures, in vivo assays, and clinical trials. This review also reports that glycitein, daidzein, and genistein are the isoflavonoids most studied in preclinical and clinical trials and displayed the most anticancer activity targeting invasion‐related proteins such as MMP‐2 and MMP‐9 and also EMT‐associated proteins. Therefore, the diversity of isoflavonoids is promising molecules to be used as chemotherapeutic in invasive cancer. In the future, more clinical trials are needed to validate the effectiveness of the various natural isoflavonoids in the treatment of invasive cancer.