Jesus Perez-Losada

• Doctor of Medicine
• University of Salamanca

Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as g...

It is imperative to identify patients with prostate cancer (PCa) who will benefit from androgen receptor signaling inhibitors that can impact quality of life upon prolonged use. Using our extensively-validated artificial-intelligence technique: cellular morphometric biomarker via machine learning (CMB-ML), we identified 13 CMBs from whole slide ima...

Background Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. Methods 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 3...

Background Luminal A tumours generally have a favourable prognosis but possess the highest 10‐year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post‐diagnosis. Identifying such patients is crucial as long‐term relapsers could benefit from extended hormone therapy, while early relapsers m...

Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer...

Only a small number of infected people are highly susceptible to schistosomiasis, showing high levels of infection or severe liver fibrosis. The susceptibility to schistosome infection is influenced by genetic background. To assess the genetic basis of susceptibility and identify the chromosomal regions involved, a backcross strategy was employed t...

Simple Summary GRB2-associated binder 1 (GAB1) is a docking protein pivotal in linking multiple stimuli to various intracellular signaling pathways. Embryonic development is disrupted in GAB1-deficient mice, and oncogenic mutations have been noted in cancer cases. In numerous types of cancer, high GAB1 expression levels correlate with a poor progno...

Introduction: Risk stratification of cutaneous squamous cell carcinoma (CSCC) is essential for managing patients. Artificial intelligence and machine learning might help stratify patients with CSCC by risk using more than solely clinical and histopathological factors. Methods: A retrospective cohort of 104 CSCCs excised with clear margins was re...

Background Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers, with a quarter recurring within five years. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers may require aggressive treat...

Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers. From those that relapse, a quarter of them do it within five years after diagnosis. Identifying such patients is crucial, as long-term relapsers could benefit from extended hormone therapy, whereas early relaps...

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CD...

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types...

CBX7 is a member of the chromobox gene family, which plays an important role in epigenetic transcriptional regulation. In this study, we found that compared to normal mammary tissues, mRNA levels of CBX7 are consistently significantly downregulated in breast cancers (BCs) across different datasets. Integrative multiomics analysis revealed the genet...

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types...

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptib...

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These mole...

BACKGROUND The development of precision medicine is essential for personalized treatment and improved clinical outcome, whereas biomarkers are critical for the success of precision therapies. AIM To investigate whether iCEMIGE (integration of CEll-morphometrics, MIcrobiome, and GEne biomarker signatures) improves risk stratification of breast canc...

Ovarian cancer (OC) is the most lethal gynecological malignancy; therefore, more effective treatments are urgently needed. We recently reported that chloroquine (CQ) increased reactive oxygen species (ROS) in OC cell lines (OCCLs), causing DNA double-strand breaks (DSBs). Here, we analyzed whether these lesions are repaired by nonhomologous end joi...

High levels of infection and severe liver fibrosis in schistosomiasis appear only in a few cases of infected people with high susceptibility. Tissue damage is caused by the inflammatory response to eggs trapped in the liver. The genetic background influences susceptibility to schistosome infection. To assess the genetic basis of susceptibility to s...

Mouse models of cancer provide a powerful tool for investigating all aspects of cancer biology. In this study, we used our recently developed machine learning approach to identify the cellular morphometric biomarkers (CMB) from digital images of hematoxylin and eosin (H&E) micrographs of orthotopic Trp53 -null mammary tumors (n = 154) and to discov...

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease...

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients wi...

Secreted angiopoietin/angiopoietin-like (ANGPT/ANGPTL) proteins are involved in many biological processes. However, the role of these proteins in human breast cancers (BCs) remains largely unclear. Here, we conducted integrated omics analyses to evaluate the clinical impact of ANGPT/ANGPTL proteins and to elucidate their biological functions. In BC...

Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the bio...

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2⁺/ERBB2⁺ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proli...

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In additio...

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been i...

Background: The new 8th edition of the American Joint Committee on Cancer (AJCC) staging system incorporates changes regarding cutaneous squamous cell carcinoma (CSCC). Objectives: We aimed to compare the 8th edition of the AJCC (AJCC-8) staging system with the previous 7th edition (AJCC-7) and the Brigham and Women's Hospital alternative stagin...

Fig. S1. FBXW7 downregulation does not influence gefitinib sensitivity of H1299 cells. Fig. S2. FBXW7 expression is silenced in PC9 cells by siFBXW7. Fig. S3. Schematic diagram of FBXW7‐mTOR signaling axis in the regulation of tumorigenesis and EGFR‐TKI sensitivity of NSCLC.

Table S1. FBXW7 alteration in lung adenocarcinomas and squamous cell carcinomas from TCGA study.

Background Cutaneous squamous cell carcinoma (cSCC) represents the most common form of skin cancer after basal cell carcinoma, and can be both locally invasive and metastatic to distant sites. Growth rate (GR) has been poorly evaluated in cSCC, despite clinical evidence suggesting that GR is an important risk factor in cSCC. Aim To analyse the inf...

The data presented in this article are related to the research paper entitled “The biological age linked to oxidative stress modifies breast cancer aggressiveness” (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. Garc...

Gefitinib, an epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI), is an effective treatment for non‐small‐cell lung cancer (NSCLC) with EGFR activating mutations, but inevitably, the clinical efficacy is impeded by the emergence of acquired resistance. The tumor suppressor gene FBXW7 modulates chemosensitivity in various human ca...

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we...

Adjuvant radiotherapy (RT) in breast cancer (BC) is often used to eradicate remaining tumor cells following surgery with the goal of maximizing local control and increasing overall survival. The current study investigated the impact of age and BC molecular subtype on overall survival after RT using a meta-analysis of the METABRIC and TCGA BC patien...

Introduction: The cardiotoxicity of anthracyclines is a complex trait. The level of cardiac damage is partly mediated by an imbalance between different intracellular signalling pathways, such as p38MAPK or PI3K / AKT, which at the same time, have been described as being important in other cardiac tissue processes. Working hypothesis: (i) Inter-indi...

Introduction: Anthracyclines are among the most widely used chemotherapeutic agents in the treatment of a variety of tumours. The identification of genetic and molecular factors responsible for the increased risk of CDA (cardiotoxicity due to anthracyclines) will contribute to a better understanding of their pathophysiology. This, in turn, could le...

Background: Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. Objectives: We aimed to identify the expression pattern of microRN...

Introduction: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers to recognize those...

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forw...

1. Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC). Universidad de Salamanca/CSIC. Salamanca, España. 2. Instituto Biosanitario de Salamanca (IBSAL). Salamanca, España. 3. Departamento de Bioquímica y Biología Molecular I. Facultad de Biología. Universidad Complutense de Madrid. Madrid, España. 4. Departamento de Medicina. Universi...

An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. Here, we present a model in which there are complex interactions at different cellular and...

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency...

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Supplementary Table S1, Supplementary Figure Legends and Supplementary Materials and Methods

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SFKs are involved in tumorigenesis and metastasis. Here we analyzed c-Src contribution to initial steps of metastasis by tetracycline-dependent expression of a specific shRNA-c-Src, which suppressed c-Src mRNA and protein levels in metastatic MDA-MB-231 cells. c-Src suppression did not alter cell proliferation or survival, but it significantly redu...

Schistosomiasis is a disease with a strong genetic component influenced by socioeconomic and ecological factors. Epidemiological studies have identified several genetic regions involved in the schistosomiasis susceptibility. However, it is not well known what physiological traits are predisposing to the disease. The study of experimental infections...

Most Schistosoma mansoni experimental infections are developed in several inbred strains of Mus musculus as definitive host. In contrast, Mus spretus is unexplored in Schistosoma infection studies. Mus spretus provides a high variation of immunological phenotypes being an invaluable tool for genetic studies and gene mapping. The aim of this study i...

Background Melanoma is responsible for almost 80% of the deaths attributed to skin cancer. Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. Objectives We hypothesized that the phenotypic heterogeneity of human cutaneous melanomas is related to their content of CD133...

Recently, it has been suggested that C2ORF40 is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40 and its functional role in breast cancers remain unclear. Here we show that C2ORF40 is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2OR...

FBXW7 acts as a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of FBXW7 expression, which could be partially attributed by the genomic deletion or mutation of FBXW7 locus, is frequently observed in various human cancers. However, the mechanisms regulating FBXW7 expression still remain poorly understood. Here...

Genomic structure of FBXW7α. 1αa, 1αc, 1αb and 1αe are additional exons identified in this study. (DOC)

The mRNA levels of Fbxw7α, Fbxw7β and Fbxw7γ in the different tissues were determined by RT-PCR analysis using corresponding primer pairs (Forward primers: Fα, Fβ, Fγ, and common reverse primer cdc4R) listed in Table S1. Normal tissues include: 1-esophagus, 2-adipose, 3-heart, 4-bladder, 5-kidney, 6-brain, 7-liver, 8-lung, 9-cervix, 10-colon, 11-sp...

The sequences of each FBXW7a 5′-UTR AS form. (DOC)

The primers used in this study. (DOC)

Differential change in mRNA expression level of FBXW7α AS forms in human prostate (A) and bladder (B) cancers. The mRNA expression profile of FBXW7α AS forms was determined by semi-quantitative RT-PCR. “M” for DNAs ladder Marker. (DOC)

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series o...

Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of hu...

Cancer is the subject of intense research around the world, but many questions about how the disease works remain unanswered. How exactly does cancer start and how do tumours grow? In fact, at present there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents ar...

Cancer susceptibility is due to interactions between inherited genetic factors and exposure to environmental carcinogens. The genetic component is constituted mainly by weakly acting low-penetrance genetic variants that interact among themselves, as well as with the environment. These low susceptibility genes can be categorized into two main groups...

Additional figures and tables. A schematic overview of the experiment, additional detailed figures supporting the eQTL analysis, a table listing eQTL detected in carcinomas, a table detailing cis- and trans-eQTL counts, a table listing genes altered more than two standard deviations from the mean in carcinomas compared to matched normal skin, and a...

Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants a...

To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development. The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy...

Comment on: Yang D, et al. Cell Cycle 2010; 9:2789-802.

Cancer is a complex and highly dynamic process. Genetically engineered mouse models (GEMs) that develop cancer are essential systems for dissecting the processes that lead to human cancer. These animal models provide a means to determine the causes of malignancy and to develop new treatments, thus representing a resource of immense potential for me...

Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. Given the fact that human cancer is diagnosed at later stages and cannot be monitored during its natural evolution, the origin of tumors has...

The acceptance of the Cancer Stem Cell (CSC) concept has revolutionized all aspects of our understanding of cancer biology, from the cellular origin of cancer to its growth and expansion, shedding new light into the interrelations of all the cellular components of the tumour and their role in its progression. From the therapeutic point of view, the...

Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-beta1 (TGF-beta1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. Thi...

Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer. Mice of the Mus spretus species are resistant to tumour development, and crosses between M. spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin...

Ataxia-Telangiectasia (A-T) is an autosomal recessive human disease characterized by genetic instability, radiosensitivity, immunodeficiency and cancer predisposition, because of mutation in both alleles of the ATM (ataxia-telangiectasia mutated) gene. The role of Atm heterozygosity in cancer susceptibility is controversial, in both human and mouse...

There are increasing data supporting the existence of a cell hierarchy within the mammary gland. At the top or this hierarchy a small population of cells with self-renewal properties maintains the tissue architecture and remodeling, and they are known as stem cells. Also, recent evidences indicate that breast cancer is originated and maintained by...

Breast cancer is a first magnitude problem of public health worldwide. There is increasing evidence that this cancer is originated in and maintained by a small population of undifferentiated cells with self-renewal properties. This small population generates a more differentiated pool of cells which represents the main mass of the tumor, resembling...

Cancer progression is due to the accumulation of recurrent genomic alterations that induce growth advantage and clonal expansion. Most of these genomic changes can be detected using the array comparative genomic hybridization (CGH) technique. The accurate classification of these genomic alterations is expected to have an important impact on transla...

The Aurora-A kinase gene is amplified in a subset of human tumors and in radiation-induced lymphomas from p53 heterozygous mice. Normal tissues from p53-/- mice have increased Aurora-A protein levels, but lymphomas from these mice exhibit heterozygous deletions of Aurora-A and/or reduced protein expression. A similar correlation between low p53 lev...

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate tha...

Although radiation can directly induce DNA damage and is a known human and animal carcinogen, the number of genetic changes in radiation-induced tumors, and the pathways responsible for generating them, are unknown. We have used high-density BAC arrays covering >95% of the mouse genome for analysis of genomic patterns of aberrations in spontaneous...

The Pten and Ras pathways are disrupted or activated, respectively, in a substantial proportion of cancers. Skin tumors induced by the classical two stage carcinogenesis protocols show consistent activating mutations of the H-ras gene, but in tumors from Pten heterozygous mice, the frequency of these mutations is markedly decreased, suggesting some...

Mouse models of cancer have provided novel insights into the timing of p53 loss during tumorigenesis. We have recently identified Fbxw7/Cdc4 as a downstream target of p53 loss that controls genomic instability and tumor development in epithelial tumors. Although p53-deficient mice primarily develop lymphomas and sarcomas, the additional loss of one...

p53 is one of the most important tumor suppressor genes in human cancer, but the roles of its homologues p63 and p73 in tumor suppression, alone or in collaboration with p53, remains controversial. Both p63 and p73 can be deregulated after DNA damage, and induce cell cycle arrest and apoptosis, but mice carrying inactive alleles of these genes do n...