RESUMO
The epithelium of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal cells surrounded by a contractile basal cell layer. The co-ordinated development of stem/progenitor cells into these luminal and basal cells is fundamentally important for breast morphogenesis. The ovarian steroid hormones, progesterone (P) and 17ß-estradiol, are critical in driving this normal breast development, yet ovarian activity has also been shown to be a major driver of breast cancer risk. We previously demonstrated that P treatment increases proliferation and augments the number of progenitor-like cells, and that the progesterone receptor (PR) is also expressed in the bipotent progenitor-enriched subfraction. Here we demonstrate that PR is expressed in a subset of CD10+ basal cells and that P stimulates this CD10+ cell compartment, which is enriched for bipotent progenitor activity. In addition, we have shown that P stimulates progenitor cells in human breast cancer cell lines and expands the cancer stem cell population via increasing the stem-like CD44+ population. As changes in cell type composition are one of the hallmark features of breast cancer progression, the demonstration that progenitor cells are stimulated by P in both normal breast and in breast cancer cells has critical implications in discerning the mechanisms of how P increases breast cancer risk.
Assuntos
Neoplasias da Mama/metabolismo , Mama/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progesterona/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula , Estradiol/administração & dosagem , Estradiol/genética , Feminino , Humanos , Receptores de Hialuronatos/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neprilisina/genética , Progesterona/genética , Receptores de Estrogênio/metabolismo , Células-Tronco/efeitos dos fármacosRESUMO
Progesterone is critical in normal breast development and its synthetic derivatives are emerging as major drivers of breast cancer risk. The recent demonstration that progesterone regulates the stem cell compartment in the murine mammary gland, despite the absence of progesterone receptor (PR) in mammary stem cells, highlights the fact that PR distribution in progenitor cell subsets in the human breast remains to be conclusively shown. By utilising two independent cell sorting strategies to fractionate cells into distinct subpopulations enriched for different cell lineage characteristics, we have demonstrated a consistent enrichment of PR transcripts, relative to estrogen receptor transcripts, in the bipotent progenitor subfraction in the normal human breast. We have also shown co-expression of both steroid hormone receptors with basal markers in a subset of human breast cells, and finally we have demonstrated that PR+ bipotent progenitor cells are estrogen-insensitive, and that estrogen regulates PR in mature luminal cells only.
Assuntos
Mama/citologia , Mama/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Animais , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular/efeitos dos fármacos , Separação Celular , Células Cultivadas , Molécula de Adesão da Célula Epitelial , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Estrogênios/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfa6/metabolismo , Queratina-14/metabolismo , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Células NIH 3T3 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Adulto JovemRESUMO
Fetal tissues from 16 spontaneous abortions, two terminations, and one perinatal death, 18 of which were associated with maternal human parvovirus B19 infection, were examined for B19 infection by histology and in situ hybridization using a digoxigenin-labeled B19-DNA probe. In 15 spontaneous abortions and one termination, erythroblasts with intranuclear inclusions (lantern cells) reacted with B19-DNA by in situ hybridization. No internal or external fetal malformations were observed. Because 13 (86.7%) spontaneous abortions with lantern cells occurred between the 20th and 28th weeks of gestation, it is postulated that B19 infection may be a particular threat to the fetus during this stage of gestation.
