Abstract
The heterogeneity of breast cancer makes current therapies challenging. Metformin, the anti-diabetic drug, has shown promising anti-cancer activities in epidemiological studies and breast cancer models. Yet, how metformin alters the normal adult breast tissue remains elusive. We demonstrate metformin intake at a clinically relevant dose impacts the hormone receptor positive (HR+) luminal cells in the normal murine mammary gland. Metformin decreases total cell number, progenitor capacity and specifically reduces DNA damage in normal HR+ luminal cells, decreases oxygen consumption rate and increases cell cycle length of luminal cells. HR+ luminal cells demonstrate the lowest levels of mitochondrial respiration and capacity to handle oxidative stress compared to the other fractions, suggesting their intrinsic susceptibility to long-term metformin exposure. Uncovering HR+ luminal cells in the normal mammary gland as the major cell target of metformin exposure could identify patients that would most benefit from repurposing this anti-diabetic drug for cancer prevention/therapy purposes.
Highlights
IntroductionThe antidiabetic drug, has shown promising anti-cancer activities in epidemiological studies and breast cancer models
The heterogeneity of breast cancer makes current therapies challenging
The mammary glands were processed using the short digestion protocol, resulting in the Sca1+CD49b+ luminal population not being clearly defined, and HR+ luminal population most likely included all of the mature HR+ luminal cells and a possible minor subset of the HR+ progenitor population
Summary
The antidiabetic drug, has shown promising anti-cancer activities in epidemiological studies and breast cancer models. We demonstrate metformin intake at a clinically relevant dose impacts the hormone receptor positive (HR+) luminal cells in the normal murine mammary gland. Uncovering HR+ luminal cells in the normal mammary gland as the major cell target of metformin exposure could identify patients that would most benefit from repurposing this anti-diabetic drug for cancer prevention/. Metformin reduces the proliferation of multiple breast cancer cell lines via inhibiting Complex I of the electron transport chain[6], and several studies have shown that metformin delays tumour onset and slows the growth of human xenografts and murine mammary cancer models[7,8,9,10]. The luminal compartment is further divided into HR+ and HR−
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