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Background  Estrogen 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 p16 Ink4a  (p16) or p18 Ink4c  (p18) is required for development of  Brca1 -deficient basal-like mammary tumors, and that mice lacking  p18  develop luminal-type mammary tumors.    Methods  A 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.    Results  Estrogen 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.    Conclusions  This 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.    Electronic supplementary material  The online version of this article (10.1186/s13058-018-0996-9) contains supplementary material, which is available to authorized users.

Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression