Project description:Age and parity are well-known factors that influence breast cancer development (1-3). Epidemiological studies have shown that women who have had multiple pregnancies are at a lower risk of developing breast cancer than women who have no history of pregnancy (4, 5). However, mechanisms that link parity and cancer protection are unclear. We discovered that CD8+ T cells with a tissue-resident memory (TRM) phenotype enriched in the mammary glands of parous women and mice compared to their virgin counterparts. Developmental kinetics revealed that these cells seeded the mammary gland during early gestation but persisted post lactation and was specific to the mammary glands. While these CD8 T cells expressed the TRM specific transcription factor Hobit, single cell transcriptomics revealed expansion of transcriptionally distinct canonical and non-canonical TRM populations, including a novel Hobit+ innate T cells (ITCs) in the parous mammary gland compared to their virgin counterparts. Furthermore, imaging analysis uncovered that the TRM like cells were associated with mammary epithelial cells and impairment in mammary gland branching during pregnancy significantly affected their differentiation or population expansion. In keeping with their association with mammary epithelial cells, all TRM subsets, including the Hobit+ITCs commonly required the cytokines TGF-β and IL-15 for their differentiation. Notably, depletion of CD103+ T cells exacerbated tumour growth in parous mice and lineage tracing experiments revealed that the canonical TRM like cells switched to an effector phenotype in tumours and contributed to tumour control. Together, we show for the first time that parity induces novel and heterogenous TRM like populations in the mammary gland that are central in providing protection against breast cancer.
Project description:Early full-term pregnancy affords lifetime protection against development of breast cancer. Parity-induced protection can be reproduced in a carcinogen-induced rat mammary carcinoma model. The molecular mechanisms of parity-induced protection against carcinogenic stimuli in rat mammary glands have not been fully characterized. In order to gain a better understanding of these molecular mechanisms, we performed gene expression analyses in parous and age-matched virgin (AMV) mammary glands of Lewis rats before and after carcinogen (N-methyl-N-nitrosourea; MNU) treatment. Keywords: other
Project description:Early full-term pregnancy affords lifetime protection against development of breast cancer. Parity-induced protection can be reproduced in a carcinogen-induced rat mammary carcinoma model. The molecular mechanisms of parity-induced protection against carcinogenic stimuli in rat mammary glands have not been fully characterized. In order to gain a better understanding of these molecular mechanisms, we performed gene expression analyses in parous and age-matched virgin (AMV) mammary glands of Lewis rats before and after carcinogen (N-methyl-N-nitrosourea; MNU) treatment.
Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=5, LMC) compared to resting, non-lactating human breast tissue (n=3, NMC). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. This data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.
Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=1, LMC) compared to resting, non-lactating human breast tissue (n=1, NMC, ran over 3 lanes of a 10x Genomics chip). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic hematopoietic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. This data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.
Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=4) compared to resting, non-lactating human breast tissue (n=4). Overall, we examined 54,323 viable high-quality cells from mixed age and parous individuals consisting of 29,078 lactation derived mammary cells (LMCs) and 25,245 non-lactation derived mammary cells (NMCs). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic hematopoietic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. In future this data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.
Project description:This study examined the effect of early pregnancy on the gene expression profile of total isolated mammary epithelial cells in mice.