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

Background: Na,HCO-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,HCO-cotransport with human breast cancer metastasis.

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 CO/HCO 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.

Loss of RPTPγ primes breast tissue for acid extrusion, promotes malignant transformation and results in early tumour recurrence and shortened survival.

Background: While cellular metabolism and acidic waste handling accelerate during breast carcinogenesis, temporal patterns of acid-base regulation and underlying molecular mechanisms responding to the tumour microenvironment remain unclear.

Methods: We explore data from human cohorts and experimentally investigate transgenic mice to evaluate the putative extracellular HCO-sensor Receptor Protein Tyrosine Phosphatase (RPTP)γ during breast carcinogenesis.

Results: RPTPγ expression declines during human breast carcinogenesis and particularly in high-malignancy grade breast cancer.

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

Intracellular Ca 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 Ca concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca release in response to purinergic and cholinergic stimuli.

Tumor-infiltrating lymphocytes predict improved overall survival after post-mastectomy radiotherapy: a study of the randomized DBCG82bc cohort.

Background: The predictive value of tumor-infiltrating lymphocytes (TILs) on the benefit from radiotherapy (RT) remains unclear. Our aim was to investigate the association between TILs and post-mastectomy RT (PMRT) regarding the risk of recurrence and survival in a randomized cohort.

Material And Methods: Stromal TILs were histologically estimated in 1011 tumors from high-risk breast cancer (BC) patients from the DBCG82bc trial.