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

Abstract

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. We explore data from human cohorts and experimentally investigate transgenic mice to evaluate the putative extracellular HCO 3 – -sensor Receptor Protein Tyrosine Phosphatase (RPTP)γ during breast carcinogenesis. RPTPγ expression declines during human breast carcinogenesis and particularly in high-malignancy grade breast cancer. Low RPTPγ expression associates with poor prognosis in women with Luminal A or Basal-like breast cancer. RPTPγ knockout in mice favours premalignant changes in macroscopically normal breast tissue, accelerates primary breast cancer development, promotes malignant breast cancer histopathologies, and shortens recurrence-free survival. In RPTPγ knockout mice, expression of Na + ,HCO 3 – -cotransporter NBCn1—a breast cancer susceptibility protein—is upregulated in normal breast tissue but, contrary to wild-type mice, shows no further increase during breast carcinogenesis. Associated augmentation of Na + ,HCO 3 – -cotransport in normal breast tissue from RPTPγ knockout mice elevates steady-state intracellular pH, which has known pro-proliferative effects. Loss of RPTPγ accelerates cellular net acid extrusion and elevates NBCn1 expression in breast tissue. As these effects precede neoplastic manifestations in histopathology, we propose that RPTPγ-dependent enhancement of Na + ,HCO 3 – -cotransport primes breast tissue for cancer development.