Abstract
BackgroundEstrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors.MethodsA genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis.ResultsEstrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.ConclusionsThis study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER.
Highlights
Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER)
We demonstrate that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of epithelial-mesenchymal transition (EMT), which are dependent on AKT activation, but independent of ER
We previously discovered that the expression of p16 and p18 along with senescence markers was increased in mammary epithelial cells (MECs) of Brca1+/− and Brca1MGKO mice [19, 23, 39]. p18−/− mice in the Balb/c background developed ER-positive luminal-type mammary tumors [37] whereas p18−/−;Brca1+/− double mutant mice formed ER-negative basal-like mammary tumors [19]
Summary
Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). Blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors. Whether and how estrogen promotes ER-negative breast cancer development and progression are poorly understood. Among others, three main subtypes: human epidermal growth factor receptor 2 (HER2)-positive, ER-positive luminal, and ER-negative basal-like breast cancers (BLBCs) [9]. Whether and how estrogen activates EMT in BRCA1-deficient, ER-negative basal-like tumor cells to promote their tumor initiation and progression remain elusive
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