Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

Multidisciplinary approach in cardiomyopathies: From genetics to advanced imaging.

Cardiomyopathies are myocardial diseases characterized by mechanical and electrical dysfunction of the heart muscle which could lead to heart failure and life-threatening arrhythmias. Certainly, an accurate anamnesis, a meticulous physical examination, and an ECG are cornerstones in raising the diagnostic suspicion. However, cardiovascular imaging techniques are indispensable to diagnose a specific cardiomyopathy, to stratify the risk related to the disease and even to track the response to the therapy. Echocardiography is often the first exam that the patient undergoes, because of its non-invasiveness, wide availability, and cost-effectiveness. Cardiac magnetic resonance imaging allows to integrate and implement the information obtained with the echography. Furthermore, cardiomyopathies' genetic basis has been investigated over the years and the list of genetic mutations deemed potentially pathogenic is expected to grow further. The aim of this review is to show echocardiographic, cardiac magnetic resonance imaging, and genetic features of several cardiomyopathies: dilated cardiomyopathy (DMC), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction cardiomyopathy (LVNC), myocarditis, and takotsubo cardiomyopathy.

Pleiotropic Effects of Direct Oral Anticoagulants in Chronic Heart Failure and Atrial Fibrillation: Machine Learning Analysis.

Oral anticoagulant therapy (OAT) for managing atrial fibrillation (AF) encompasses vitamin K antagonists (VKAs, such as warfarin), which was the mainstay of anticoagulation therapy before 2010, and direct-acting oral anticoagulants (DOACs, namely dabigatran etexilate, rivaroxaban, apixaban, edoxaban), approved for the prevention of AF stroke over the last thirteen years. Due to the lower risk of major bleeding associated with DOACs, anticoagulant switching is a common practice in AF patients. Nevertheless, there are issues related to OAT switching that still need to be fully understood, especially for patients in whom AF and heart failure (HF) coexist. Herein, the effective impact of the therapeutic switching from warfarin to DOACs in HF patients with AF, in terms of cardiac remodeling, clinical status, endothelial function and inflammatory biomarkers, was assessed by a machine learning (ML) analysis of a clinical database, which ultimately shed light on the real positive and pleiotropic effects mediated by DOACs in addition to their anticoagulant activity.

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

Dapagliflozin protects the kidney in a non-diabetic model of cardiorenal syndrome.

Cardiorenal syndrome encompasses a spectrum of disorders involving heart and kidney dysfunction, and sharing common risk factors, such as hypertension and diabetes. Clinical studies have shown that patients with and without diabetes may benefit from using sodium-glucose cotransporter 2 inhibitors to reduce the risk of heart failure and ameliorate renal endpoints. Because the underlying mechanisms remain elusive, we investigated the effects of dapagliflozin on the progression of renal damage, using a model of non-diabetic cardiorenal disease. Dahl salt-sensitive rats were fed a high-salt diet for five weeks and then randomized to dapagliflozin or vehicle for the following six weeks. After treatment with dapagliflozin, renal function resulted ameliorated as shown by decrease of albuminuria and urine albumin-to-creatinine ratio. Functional benefit was accompanied by a decreased accumulation of extracellular matrix and a reduced number of sclerotic glomeruli. Dapagliflozin significantly reduced expression of inflammatory and endothelial activation markers such as NF-κB and e-selectin. Upregulation of pro-oxidant-releasing NADPH oxidases 2 and 4 as well as downregulation of antioxidant enzymes were also counteracted by drug treatment. Our findings also evidenced the modulation of both classic and non-classic renin-angiotensin-aldosterone system (RAAS), and effects of dapagliflozin on gene expression of ion channels/transporters involved in renal homeostasis. Thus, in a non-diabetic model of cardiorenal syndrome, dapagliflozin provides renal protection by modulating inflammatory response, endothelial activation, fibrosis, oxidative stress, local RAAS and ion channels.

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation.

Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco-/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine-induced increases in intracellular Ca2+ concentrations were unaffected and ATP- and UTP-induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity-evaluated by bromodeoxyuridine incorporation-in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death-identified with ethidium homodimer-1 staining-in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.

A machine learning algorithm to analyse the effects of vaccination on COVID-19 mortality.

The coronavirus disease 2019 (COVID-19), with new variants, continues to be a constant pandemic threat that is generating socio-economic and health issues in manifold countries. The principal goal of this study is to develop a machine learning experiment to assess the effects of vaccination on the fatality rate of the COVID-19 pandemic. Data from 192 countries are analysed to explain the phenomena under study. This new algorithm selected two targets: the number of deaths and the fatality rate. Results suggest that, based on the respective vaccination plan, the turnout in the participation in the vaccination campaign, and the doses administered, countries under study suddenly have a reduction in the fatality rate of COVID-19 precisely at the point where the cut effect is generated in the neural network. This result is significant for the international scientific community. It would demonstrate the effective impact of the vaccination campaign on the fatality rate of COVID-19, whatever the country considered. In fact, once the vaccination has started (for vaccines that require a booster, we refer to at least the first dose), the antibody response of people seems to prevent the probability of death related to COVID-19. In short, at a certain point, the fatality rate collapses with increasing doses administered. All these results here can help decisions of policymakers to prepare optimal strategies, based on effective vaccination plans, to lessen the negative effects of the COVID-19 pandemic crisis in socioeconomic and health systems.

Arrhythmic myocarditis in an adolescent male: A unique presentation of multi-organ inflammatory syndrome (MIS-C).

Although children with Covid-19 generally present with mild symptoms or are often asymptomatic, there is increasing recognition of a delayed multi-organ inflammatory syndrome (MIS-C) following SARS-CoV-2 infection. We report the case of MIS-C associated arrhythmic myocarditis which recovered after anti-inflammatory therapy and immunoglobulin infusion.

The Impact of the COVID-19 Pandemic on Surgical Management of Breast Cancer: Global Trends and Future Perspectives.

INTRODUCTION: The rapid spread of COVID-19 across the globe is forcing surgical oncologists to change their daily practice. We sought to evaluate how breast surgeons are adapting their surgical activity to limit viral spread and spare hospital resources. METHODS: A panel of 12 breast surgeons from the most affected regions of the world convened a virtual meeting on April 7, 2020, to discuss the changes in their local surgical practice during the COVID-19 pandemic. Similarly, a Web-based poll based was created to evaluate changes in surgical practice among breast surgeons from several countries. RESULTS: The virtual meeting showed that distinct countries and regions were experiencing different phases of the pandemic. Surgical priority was given to patients with aggressive disease not candidate for primary systemic therapy, those with progressive disease under neoadjuvant systemic therapy, and patients who have finished neoadjuvant therapy. One hundred breast surgeons filled out the poll. The trend showed reductions in operating room schedules, indications for surgery, and consultations, with an increasingly restrictive approach to elective surgery with worsening of the pandemic. CONCLUSION: The COVID-19 emergency should not compromise treatment of a potentially lethal disease such as breast cancer. Our results reveal that physicians are instinctively reluctant to abandon conventional standards of care when possible. However, as the situation deteriorates, alternative strategies of de-escalation are being adopted. IMPLICATIONS FOR PRACTICE: This study aimed to characterize how the COVID-19 pandemic is affecting breast cancer surgery and which strategies are being adopted to cope with the situation.

Assessing a fossil fuels externality with a new neural networks and image optimisation algorithm: the case of atmospheric pollutants as confounders to COVID-19 lethality.

This paper demonstrates how the combustion of fossil fuels for transport purpose might cause health implications. Based on an original case study [i.e. the Hubei province in China, the epicentre of the coronavirus disease-2019 (COVID-19) pandemic], we collected data on atmospheric pollutants (PM2.5, PM10 and CO2) and economic growth (GDP), along with daily series on COVID-19 indicators (cases, resuscitations and deaths). Then, we adopted an innovative Machine Learning approach, applying a new image Neural Networks model to investigate the causal relationships among economic, atmospheric and COVID-19 indicators. Empirical findings emphasise that any change in economic activity is found to substantially affect the dynamic levels of PM2.5, PM10 and CO2 which, in turn, generates significant variations in the spread of the COVID-19 epidemic and its associated lethality. As a robustness check, the conduction of an optimisation algorithm further corroborates previous results.

NO2 levels as a contributing factor to COVID-19 deaths: The first empirical estimate of threshold values.

This study represents the first empirical estimation of threshold values between nitrogen dioxide (NO2) concentrations and COVID-19-related deaths in France. The concentration of NO2 linked to COVID-19-related deaths in three major French cities were determined using Artificial Neural Networks experiments and a Causal Direction from Dependency (D2C) algorithm. The aim of the study was to evaluate the potential effects of NO2 in spreading the epidemic. The underlying hypothesis is that NO2, as a precursor to secondary particulate matter formation, can foster COVID-19 and make the respiratory system more susceptible to this infection. Three different neural networks for the cities of Paris, Lyon and Marseille were built in this work, followed by the application of an innovative tool of cutting the signal from the inputs to the selected target. The results show that the threshold levels of NO2 connected to COVID-19 range between 15.8 µg/m3 for Lyon, 21.8 µg/m3 for Marseille and 22.9 µg/m3 for Paris, which were significantly lower than the average annual concentration limit of 40 µg/m³ imposed by Directive 2008/50/EC of the European Parliament.

Revascularization rates with coronary angioplasty and mortality in type 2 myocardial infarction: A meta-regression analysis.

BACKGROUND: Percutaneous coronary intervention (PCI) represents the best therapeutic option for type-1 myocardial infarction (T1MI) in the majority of clinical settings; its role in the treatment of type-2 myocardial infarction (T2MI), however, remains unclear. We therefore sought to assess in a meta-regression analysis the impact of PCI rates on mortality in patients with T2MI according to available observational studies. METHODS: We performed a meta-regression analysis including all the studies involving in-patients affected by T2MI. We excluded studies not reporting the rate of T2MI patients undergoing PCI and not specifying absolute in-hospital or 1-year all-cause mortality. In the meta-regression analysis we used the in-hospital mortality and 1-year mortality as dependent variables and the rate of PCI as independent; regression was weighted for studies' size. RESULTS: After careful examination, 8 studies were selected for the assessment of in-hospital mortality and 8 for 1-year-mortality. We included 3155 and 3756 in-patients for in-hospital and 1-year mortality respectively. At meta-regression analysis, a borderline correlation between PCI rate and in-hospital mortality (p 0.05) and a statistically significant correlation with 1-year mortality (p < 0.01) in T2MI patients were found. CONCLUSIONS: In a meta-regression analysis higher rates of PCI on T2MI in-patients were associated with lower mortality rates both in-hospital and at 1 year. Whether this association is related to the direct effect of PCI or better general conditions of T2MI patients undergoing a PCI still remains unclear.

Can biomass energy curtail environmental pollution? A quantum model approach to Germany.

This paper aims to investigate the causal relationship among renewable energy technologies, biomass energy consumption, per capita GDP, and CO2 emissions for Germany. We constructed an innovative algorithm, the Quantum model, and applied it with Machine Learning experiments - through a software capable of emulating a quantum system - to data over the period of 1990-2018. This process is possible after eliminating the "irreversibility" of classical computations (unitary transformations) by making the process "reversible". The empirical findings support the powerful role of biomass energy in reducing carbon dioxide emissions, although the effect of renewable energy technology displays a much stronger magnitude. Moreover, income remains an important determinant of environmental pollution in Germany.

The nexus between COVID-19 deaths, air pollution and economic growth in New York state: Evidence from Deep Machine Learning.

The aim of this paper is to assess the relationship between COVID-19-related deaths, economic growth, PM10, PM2.5, and NO2 concentrations in New York state using city-level daily data through two Machine Learning experiments. PM2.5 and NO2 are the most significant pollutant agents responsible for facilitating COVID-19 attributed death rates. Besides, we found only six out of many tested causal inferences to be significant and true within the AUPRC analysis. In line with the causal findings, a unidirectional causal effect is found from PM2.5 to Deaths, NO2 to Deaths, and economic growth to both PM2.5 and NO2. Corroborating the first experiment, the causal results confirmed the capability of polluting variables (PM2.5 to Deaths, NO2 to Deaths) to accelerate COVID-19 deaths. In contrast, we found evidence that unsustainable economic growth predicts the dynamics of air pollutants. This shows how unsustainable economic growth could increase environmental pollution by escalating emissions of pollutant agents (PM2.5 and NO2) in New York state.

The relationship between air pollution and COVID-19-related deaths: An application to three French cities.

Being heavily dependent to oil products (mainly gasoline and diesel), the French transport sector is the main emitter of Particulate Matter (PMs) whose critical levels induce harmful health effects for urban inhabitants. We selected three major French cities (Paris, Lyon, and Marseille) to investigate the relationship between the Coronavirus Disease 19 (COVID-19) outbreak and air pollution. Using Artificial Neural Networks (ANNs) experiments, we have determined the concentration of PM2.5 and PM10 linked to COVID-19-related deaths. Our focus is on the potential effects of Particulate Matter (PM) in spreading the epidemic. The underlying hypothesis is that a pre-determined particulate concentration can foster COVID-19 and make the respiratory system more susceptible to this infection. The empirical strategy used an innovative Machine Learning (ML) methodology. In particular, through the so-called cutting technique in ANNs, we found new threshold levels of PM2.5 and PM10 connected to COVID-19: 17.4 µg/m3 (PM2.5) and 29.6 µg/m3 (PM10) for Paris; 15.6 µg/m3 (PM2.5) and 20.6 µg/m3 (PM10) for Lyon; 14.3 µg/m3 (PM2.5) and 22.04 µg/m3 (PM10) for Marseille. Interestingly, all the threshold values identified by the ANNs are higher than the limits imposed by the European Parliament. Finally, a Causal Direction from Dependency (D2C) algorithm is applied to check the consistency of our findings.

Validity of Danish Breast Cancer Group (DBCG) registry data used in the predictors of breast cancer recurrence (ProBeCaRe) premenopausal breast cancer cohort study.

BACKGROUND: Validation studies of the Danish Breast Cancer Group (DBCG) registry show good agreement with medical records for adjuvant treatment data, but inconsistent recurrence information. No studies have validated changes in menopausal status or endocrine therapy during follow-up. In a longitudinal study, we validated DBCG data using medical records as the gold standard. MATERIAL AND METHODS: From a cohort of 5959 premenopausal women diagnosed during 2002-2010 with stage I-III breast cancer, we selected 151 patients - 77 estrogen-receptor-positive and 74 estrogen-receptor-negative - from three hospitals. We assessed the validity of DBCG registry data on patient, tumor, and treatment factors, and follow-up information on menopausal transition, changes in endocrine therapy, and recurrence. We computed positive predictive values (PPVs) with 95% confidence intervals (95%CI). RESULTS: Agreement was near perfect for tumor size, lymph node involvement, receptor status, surgery type, and receipt of radiotherapy, chemotherapy, or tamoxifen treatment. The PPV for a change in endocrine therapy in the DBCG was 96% (95%CI = 83, 100). The PPV for menopausal transition was 61% (95%CI = 42, 77). The PPV for DBCG-recorded recurrence was 100%. However, of 19 patients who had a recurrence documented in their medical record, 13 had the recurrence registered in DBCG. CONCLUSIONS: DBCG data are valid for most epidemiological studies of breast cancer treatment. Data on menopausal transition may be less valid, though this interpretation depends on the suitability of medical records for making this assessment. Although recurrence is missing for some, this would not bias most ratio measures of association.

STEMI and NSTEMI ACS in a 30-Year-Old Patient: An Extremely Rare Complication of a Left Atrial Myxoma.

Primary cardiac tumors are a rare entity whose incidence in the general population ranges from 0.0017% to 0.28%. Myxomas represent nearly half of all primary benign cardiac tumors and they prevalently affect female patients. Embolic manifestation is rare with a reported incidence of 0.06%.We present the case of a 30-year-old male patient with acute anterolateral infarction caused by total occlusion of the left anterior descending artery as a consequence of a left atrial myxoma embolization. Urgent surgical resection of the mass didn't avoid early recurrence of atrial myxoma, whose second presentation was again myocardial infarction.This case alerts physicians to "unusual" myocardial infarction patients, when atherosclerotic pathogenesis appears unlikely. In these cases early echocardiographic evaluation should be mandatory and atrial myxoma should be considered among the possible causes. Complete surgical resection is the only effective therapeutic option to improve prognosis; the chance of tumor recurrence should dictate careful research for additional myxomas during surgery and stricter follow-up planning.

Primary breast sarcoma: A retrospective study over 35 years from a single institution.

AIM: The aim of this study was to contribute to the collected knowledge of prognostic factors in primary breast sarcomas (PBS) to the benefit of possible future prospective studies and therapeutic guidelines. METHOD: All patients with pathologically verified PBS in the period of 1979-2014 were extracted from a hospital-based database at Aarhus University Hospital. All records were reviewed for patient and tumor characteristics. Primary endpoints were overall survival, disease-free survival (DFS) and disease-specific survival (DSS). Adjustments were made for age, tumor location, surgical strategy, size, histological classification, prior radiation and grade. Prognostic factors were determined by the use of Cox proportional hazard ratio. RESULTS: In total 42 patients were identified. Surgical resection was the main method of treatment. Nineteen (45%) patients were initially selected for lumpectomy, of these 68% needed at least one re-excision to attain wide margins. In total 55% experienced recurrence, loco regional in 43%. Five-years overall survival was 49%, five-year DFS was 48% and five-year DSS was 40%. Significant prognostic factors were size and grade. A trend towards better survival in those with superficial tumors was observed as well as an increased incidence in radiation-induced angiosarcoma (AS) of the breast, however, prognosis was no different from non-radiation-induced AS. CONCLUSION: Prognostic factors in PBS patients were size and grade with a trend towards better survival in those with superficial tumors. There was no difference in survival between radiation-induced and spontaneous breast sarcomas. High rate of local recurrence suggests the need for aggressive surgical approach or the routine addition of postoperative radiotherapy in those selected for breast conserving surgery (BCS).

Na+,HCO3- -cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane.

Metabolic and biochemical changes during breast carcinogenesis enhance cellular acid production. Extrusion of the acid load from the cancer cells raises intracellular pH, while it decreases extracellular pH creating an inverted pH gradient across the plasma membrane compared to normal cells and promoting cancer cell metabolism, proliferation, migration, and invasion. We investigated the effects of breast carcinogenesis on the mechanisms of cellular pH control using multicellular epithelial organoids freshly isolated from human primary breast carcinomas and matched normal breast tissue. Intracellular pH was measured by fluorescence microscopy, while protein expression was investigated by immunofluorescence imaging and immunoblotting. We found that cellular net acid extrusion increased during human breast carcinogenesis due to enhanced Na(+),HCO3 (-)-cotransport, which created an alkaline shift (~0.3 units of magnitude) in steady-state intracellular pH of human primary breast carcinomas compared to normal breast tissue. Na(+)/H(+)-exchange activity and steady-state intracellular pH in the absence of CO2/HCO3 (-) were practically unaffected by breast carcinogenesis. These effects were evident under both acidic (pH 6.8, representative of the tumor microenvironment) and physiological (pH 7.4) extracellular conditions. Protein expression of the Na(+),HCO3 (-)-cotransporter NBCn1 (SLC4A7), which has been linked to breast cancer susceptibility in multiple genome-wide association studies, was twofold higher in human breast carcinomas compared to matched normal breast tissue. Protein expression of the Na(+)/H(+)-exchanger NHE1 (SLC9A1) was markedly less affected. We propose that upregulated NBCn1 during human breast carcinogenesis contributes to the characteristic acid distribution within human breast carcinomas and thereby plays a pathophysiological role for breast cancer development and progression.