Identifying the murine mammary cell target of metformin exposure.
PMID 31123716 · Communications biology · 2019 · DOI 10.1038/s42003-019-0439-x
Authors: Mona Shehata; Hyeyeon Kim; Ravi Vellanki; Paul D Waterhouse; Mathepan Mahendralingam; Alison E Casey; Marianne Koritzinsky; Rama Khokha
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.
Animals; Apoptosis; Cell Cycle; Cell Lineage; Cell Separation; DNA Damage; Female; Flow Cytometry; Hypoglycemic Agents; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Metformin; Mice; Receptors, Estrogen
Cite
Mona Shehata; Hyeyeon Kim; Ravi Vellanki; Paul D Waterhouse; Mathepan Mahendralingam; Alison E Casey; Marianne Koritzinsky; Rama Khokha. Identifying the murine mammary cell target of metformin exposure. Communications biology (2019). PMID 31123716. DOI 10.1038/s42003-019-0439-x.