Tumorspheres as In Vitro Model for Identifying Predictive Chemoresistance and Tumor Aggressiveness Biomarkers in Breast and Colorectal Cancer.

Chemoresistance remains a major challenge in the treatment of breast and colorectal cancer. For this reason, finding reliable predictive biomarkers of response to chemotherapy has become a significant research focus in recent years. However, validating in vitro results may be problematic due to the outcome heterogeneity.

Unraveling malignant phenotype of peritumoral tissue: transcriptomic insights into early-stage breast cancer.

Background: Early-stage invasive ductal carcinoma displays high survival rates due to early detection and treatments. However, there is still a chance of relapse of 3-15% after treatment. The aim of this study was to uncover the distinctive transcriptomic characteristics and monitoring prognosis potential of peritumoral tissue in early-stage cases.

Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies.

Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others.

Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.

Unlabelled: Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated.

Vitamin D analogues exhibit antineoplastic activity in breast cancer patient-derived xenograft cells.

Despite advances in breast cancer (BC) treatment, its mortality remains high due to intrinsic or acquired resistance to therapy. Several ongoing efforts are being made to develop novel drugs to treat this pathology with the aim to overcome resistance, prolong patient survival and improve their quality of life. We have previously shown that the non-hypercalcemic vitamin D analogues EM1 and UVB1 display antitumor effects in preclinical studies employing conventional cell lines and animal models developed from these cells.

The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1.

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease.

Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells.

Background: The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy.

Methods: A panel of wild-type and mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were used, as well as chronic lymphocytic leukemia (CLL) patients with different TP53 gene status. The effects of mutant p53 were evaluated by confocal microscopy, reactive oxygen species production assay, immunoblotting, and quantitative reverse transcription polymerase chain reaction after cellular transfection.

Resistance to the Antibody-Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity.

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2 breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2 clones exhibiting stable drug refractoriness and Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1.

Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition.

Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling.

The presence of Estrogen Receptor β modulates the response of breast cancer cells to therapeutic agents.

Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERβ increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERα/ERβ ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM).

The Phytoestrogen Genistein Affects Breast Cancer Cells Treatment Depending on the ERα/ERβ Ratio.

Genistein (GEN) is a phytoestrogen found in soybeans. GEN exerts its functions through its interaction with the estrogen receptors (ER), ERα and ERβ, and we previously reported that the ERα/ERβ ratio is an important factor to consider in GEN-treated breast cancer cells. The aim of this study was to investigate the effects of GEN in breast cancer cells with different ERα/ERβ ratio: MCF-7 (high ratio), T47D (low ratio), and MCF-7 overexpressing ERβ (MCF7 + ERβ) treated with cisplatin (CDDP), paclitaxel (PTX) or tamoxifen (TAM).

Chronic-leptin attenuates Cisplatin cytotoxicity in MCF-7 breast cancer cell line.

Background/aims: Large-scale epidemiological studies support a correlation between obesity and breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play a significant role in mammary tumor formation and progression. Moreover, regulation of oxidative stress is another important factor in both tumor development and responses to anticancer therapies.

UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress.

Modulation of oxidative stress in cancer cells plays an important role in the study of the resistance to anticancer therapies. Uncoupling protein 2 (UCP2) may play a dual role in cancer, acting as a protective mechanism in normal cells, while its overexpression in cancer cells could confer resistance to chemotherapy and a higher survival through downregulation of ROS production. Thus, our aim was to check whether the inhibition of UCP2 expression and function increases oxidative stress and could render breast cancer cells more sensitive to cisplatin (CDDP) or tamoxifen (TAM).

Phytoestrogens and mitochondrial biogenesis in breast cancer. Influence of estrogen receptors ratio.

Phytoestrogens were originally identified as compounds having a close similarity in structure to estrogens and harboring weak estrogen activity. The interest in phytoestrogens as potential therapeutic agents has recently risen in the field of oncology, since population based studies have linked phytoestrogens consumption with a decreased risk of mortality due to several types of cancer. This review departs from the main focus of these articles by describing recent advances in our understanding of phytoestrogen potential action on mitochondria, specifically on mitochondrial biogenesis, dynamics and functionality, as well as mitoptosis in breast cancer.

Genistein modulates proliferation and mitochondrial functionality in breast cancer cells depending on ERalpha/ERbeta ratio.

Breast cancer is the most common malignancy in women of developed countries. The aim of this study was to investigate whether genistein, a soy phytoestrogen, and 17β-estradiol (E2) could have effects on the cell cycle and mitochondrial function and dynamics. Three human breast cancer cell lines with different estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) ratio were used: MCF-7 (high ERα/ERβ ratio), T47D (low ERα/ERβ ratio) and MDA-MB-231 (ER-negative).

Genistein modulates oxidative stress in breast cancer cell lines according to ERα/ERβ ratio: effects on mitochondrial functionality, sirtuins, uncoupling protein 2 and antioxidant enzymes.

Genistein is a biologically active isoflavone with estrogenic activity and can be found in a variety of soy products. This natural compound displays a wide array of biological activities, but it is best known for its ability to inhibit cancer progression, especially for hormone-related ones such as breast cancer. Genistein has been shown to bind both the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ), although it has a higher affinity for the ERβ.

The over-expression of ERbeta modifies estradiol effects on mitochondrial dynamics in breast cancer cell line.

Mitochondrial biogenesis and function are under the control of 17β-estradiol, which acts through two distinct estrogen receptors (alpha or beta), and the estrogen receptors ratio can determine the final effect of 17β-estradiol on mitochondria. Our aim was to study the effects of 17β-estradiol on mitochondrial biogenesis, dynamics and function in breast cancer cell lines with different estrogen receptors ratios. Mitochondrial biogenesis was increased in MDA-MB-231 (with only estrogen receptor beta expression), T47D (normal estrogen receptors ratio) and MCF-7 (highest estrogen receptors ratio) breast cancer cell lines, in response to different mitochondrial and cellular status.

The oxidative stress in breast tumors of postmenopausal women is ERα/ERβ ratio dependent.

Estrogen receptor status is a diagnostic parameter in breast cancer treatment. Estrogen receptor presence is related to a better prognosis because the principal treatments attacking breast cancer tumors have their action site directed at the estrogen receptor. However, the two different subtypes of estrogen receptor, ERα and ERβ, have different functions.

Initial activation status of the antioxidant response determines sensitivity to carboplatin/paclitaxel treatment of ovarian cancer.

Background/aim: Ovarian carcinoma is the main cause of gynecological cancer related deaths. The aim of this study was to determine the activation status of the antioxidant response in samples of ovarian serous carcinoma from paraffin-embedded biopsies and compare them with the response of patients to carboplatin-paclitaxel treatment.

Materials And Methods: Estrogen receptor alpha (ERα), antioxidant enzymes, and uncoupling protein (UCP) levels were analyzed by western blotting and the presence of estrogen receptor beta (ERβ) was investigated by immunohistochemistry (IHC).

Mitochondrial dynamics is affected by 17β-estradiol in the MCF-7 breast cancer cell line. Effects on fusion and fission related genes.

Mitochondrial dynamics, specifically fusion and fission processes, maintain mitochondria integrity and function, yet at this time, effect of estrogens on fusion and fission in breast cancer cell lines has not been studied. The aim of this study was to characterize the effect of 17β-estradiol on fusion and fission-related genes, as well as on mitochondria proliferation and function. We used MCF-7 breast cancer cell line, which is estrogen sensitive (estrogen receptor positive).

The ERalpha/ERbeta ratio determines oxidative stress in breast cancer cell lines in response to 17beta-estradiol.

The effects of 17beta-estradiol (E2) are mediated through activation of estrogen receptors (ER): ERalpha and ERbeta. It is known that ERalpha/ERbeta ratio is higher in breast tumors than in normal tissue. Since antioxidant enzymes and uncoupling proteins (UCPs) are reactive oxygen species (ROS) production and mitochondrial biogenesis regulators, our aim was to study the E2-effect on oxidative stress, antioxidant enzyme expression, and UCPs in breast cancer cell lines with different ERalpha/ERbeta ratios.

The effects of 17β-estradiol on mitochondrial biogenesis and function in breast cancer cell lines are dependent on the ERα/ERβ ratio.

Background/aims: 17β-estradiol (E2) is a risk factor for the development of breast cancer, and cause tumorigenesis in epithelial breast cells. Moreover, E2 has distinct effects on different tissues that are attributed to the presence of two estrogen receptor isoforms, ERα and ERβ.

Methods: The effect of E2 on mitochondrial biogenesis and function was investigated in two breast cancer cell lines with different estrogen receptor ratios, MCF-7 (high ERα/ERβ ratio) and T47D (low ERα/ERβ ratio) cell lines treated with physiological concentrations of E2 (1 nM).