Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands

Rank signaling pathway regulates mammary gland homeostasis and epithelial cell differentiation. Although Rank receptor is expressed by basal cells and luminal progenitors, its role in each individual cell lineage remains unclear. By combining temporal/lineage specific Rank genetic deletion with lineage tracing techniques, we found that loss of luminal Rank reduces the luminal progenitor pool and leads to aberrant alveolar-like differentiation with high protein translation capacity in virgin mammary glands. These Rank-deleted luminal cells are unable to expand during the first pregnancy, leading to lactation failure and impairment of protein synthesis potential in the parous stage. The unfit parous Rank-deleted luminal cells in the alveoli are progressively replaced by Rank-proficient cells early during the second pregnancy, thereby restoring lactation. Transcriptomic analysis and functional assays point to the awakening of basal bipotency after pregnancy by the induction of Rank/NF-kappa B signaling in basal parous cell to restore lactation and tissue homeostasis. Rocha and co-authors show that loss of luminal Rank signaling causes abnormal alveolar differentiation and lactation failure. Subsequent pregnancies activate bipotency in basal cells, replacing unfit luminal cells, and restoring lactation

The altered transcriptome and DNA methylation profiles of docetaxel resistance in breast cancer PDX models

Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and -resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC. IMPLICATIONS: Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness

Estudio del estrés oxidativo inducido por citotóxicos en líneas celulares de cáncer de colon

[spa] El estrés oxidativo es un factor fundamental para el desarrollo y el tratamiento del cáncer colorrectal. Se está investigando el uso de antioxidantes como la genisteína (GEN) en el tratamiento de diferentes tipos de cáncer. En este trabajo nos hemos propuesto estudiar el efecto de la GEN en concentraciones fisiológicas como coadyuvante dietético del tratamiento de líneas celulares de cáncer de colon en diferente estadio tumoral: HT29 (cáncer primario) y SW620 (cáncer metastásico). En una primera fase se ha evaluado el efecto del tratamiento con 5-FU, IRI y OXA, así como de la GEN, para determinar el fármaco más efectivo y seleccionar la dosis a probar del mismo y de la GEN. Se ha observado que hay un descenso de la viabilidad celular a medida que aumenta la concentración de fármaco que se relaciona un incremento de las especies reactivas de oxígeno (ROS). El 5-FU es más efectivo en HT29 y OXA e IRI en SW620. Se ha podido observar que la GEN junto a OXA inducen de forma sinérgica la muerte celular en las células metastásicas SW620. La suplementación con GEN no cambia el nivel de ROS producido por el OXA. Se especula por un nuevo mecanismo producido por la interacción GEN y OXA e independiente de ROS. En la línea de tumor primario HT29 no hay un efecto sinérgico de los dos fármacos.[eng] Oxidative stress is a key factor in the development and treatment of colorectal cancer. The use of antioxidants such as genistein (GEN) in the treatment of several types of cancer is being investigated. In this study we decided to determine the effect of GEN in physiologic concentrations as a dietary coadjuvant of the treatment of colon cancer cell lines in different stages of cancer: HT29 (primary tumour) and SW620 (metastatic tumour). First, the effect of the treatment with 5-FU, IRI and OXA, as well as of GEN, has been assessed in order to determine the most effective drug and choose the dose of drug and GEN to be tested. It has been observed that there is a decrease in cell viability as the concentration of the drug is increased, which is related to an increase in reactive oxygen species (ROS). 5-FU is more effective in HT29 and OXA and IRI in SW620. It has been observed that GEN along with OXA synergistically induce cell death in the metastatic line SW620. The supplementation with GEN doesn’t change the level of ROS produced by OXA. A new mechanism produced by the interaction between GEN and OXA and independent of ROS has been speculated. In the primary tumour cell line HT29 there is not a synergistic effect of the two drugs

Mitochondrial functionality is regulated by alkylphosphocholines in human colon cancer cells

[eng] Perifosine is a type of alkylphosphocholines (APCs), a group of antiproliferative drugs that inhibit the growth of cancer cells without targeting DNA. In contrast to chemotherapeutic drugs, these lipophilic agents are targeted to the cell membranes and induced cell death by a controversial mechanism. It has been observed that during cancer progression there is an alteration in mitochondrial function and oxidative stress. The aim of this study was to determine the effect of perifosine in mitochondrial functionality and ROS production in human colon cancer cells HT29 and SW620. For this purpose, we determined parameters of H2O2production, cardiolipin content, Δψm determination and protein levels of OXPHOS, UCP2 and PGC-1α. Results show that perifosine caused an increase in Δψm and it is correlated to the reduction in the UCP2 levels. Besides, the treatment produces an increase in the ROS production and an unbalance in the proteins of respiratory chain. Biomarkers of mitochondrial biogenesis such as the cardiolipin content and PGC-1α are increased by the treatment. In conclusion, the anticancer effect of perifosine could be related to the deregulation of mitochondrial homeostasis in the cancer cell.[spa] La perifosina forma parte del grupo de las alquilfosfocolinas, un grupo de agentes antiproliferativos que inhiben el crecimiento de células cancerígenas sin dañar el ADN. En contraste con otras drogas quimioterapéuticas, estos agentes lipofílicos se insertan en las membranas celulares de la célula e inducen la muerte celular por un mecanismo poco conocido. Durante la progresión del cáncer se ha demostrado alteraciones en la función mitocondrial y el estrés oxidativo. El objetivo de este estudio es determinar el efecto de la perifosina en la función mitocondrial y la producción de ROS en las líneas de cáncer de colon humano HT29 y SW620. Por este motivo, se determinó la producción de H2O2, el contenido de cardiolipina, el potencial de membrana y los niveles proteicos de OXPHOS, UCP2 y PGC-1α. Los resultados muestran que la perifosina produce un aumento del potencial de membrana mitocondrial que se relaciona con un descenso de UCP2. Además, el tratamiento incrementa la producción de ROS y produce un desbalance en los niveles proteicos de la cadena respiratoria. Biomarcadores de biogénesis mitocondrial como el contenido de cardiolipina y los niveles de PGC-1α aumentaron con el tratamiento. En conclusión, parece que el efecto anticancerígeno de la perifosina podría estar relacionado con una desregulación de la homeostasis de la mitocondria en la célula cancerígena