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Inhibition of Estrogen Signaling Reduces the Incidence of BRCA1-associated Mammary Tumor Formation.

ABSTRACT: BRCA1-deficient breast cancer is a very well-known hereditary cancer. However, except for resection of normal mammary glands and ovaries, there is no acceptable measure for proactively preventing tumor development. Importantly, inherited BRCA1 mutations are closely associated with tumors in hormone-responsive tissues. Here, we examined the effects of estrogen on the accumulation of genetic instabilities upon loss of BRCA1, and assessed the contribution of estrogen signaling to the incidence and progression of Brca1-mutated mammary tumors. Our in vitro studies showed that treatment of BRCA1-depleted breast cancer cells with estrogen induced proliferation. Additionally, estrogen reduced the ability of these BRCA1-knockdown cells to sense radiation-induced DNA damage and also facilitated G1/S progression. Moreover, long-term treatment of Brca1-mutant (Brca1co/coMMTV-Cre) mice with the selective estrogen receptor (ER)-? degrader, fulvestrant, decreased the tumor formation rate from 64% to 36%, and also significantly reduced mammary gland density in non-tumor-bearing mice. However, in vivo experiments showed that fulvestrant treatment did not alter the progression of ER-positive Brca1-mutant tumors, which were frequently identified in the aged population and showed less aggressive tendencies. These findings enhance our understanding of how ER-? signaling contributes to BRCA1-deficient mammary tumors and provide evidence suggesting that targeted inhibition of ER-? signaling may be useful for the prevention of BRCA1-mutated breast cancer.

SUBMITTER: Baek HJ

PROVIDER: S-EPMC6216038 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Inhibition of Estrogen Signaling Reduces the Incidence of BRCA1-associated Mammary Tumor Formation.

Baek Hye Jung HJ Kim Sun Eui SE Choi Eun Kyung EK Kim Jong Kwang JK Shin Dong Hoon DH Park Eun Jung EJ Kim Tae Hyun TH Kim Joo-Young JY Kim Kwang Gi KG Deng Chu-Xia CX Kim Sang Soo SS

International journal of biological sciences 20181003 12

BRCA1-deficient breast cancer is a very well-known hereditary cancer. However, except for resection of normal mammary glands and ovaries, there is no acceptable measure for proactively preventing tumor development. Importantly, inherited BRCA1 mutations are closely associated with tumors in hormone-responsive tissues. Here, we examined the effects of estrogen on the accumulation of genetic instabilities upon loss of BRCA1, and assessed the contribution of estrogen signaling to the ...[more]

PMID: 30416390

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Project description:BACKGROUND: Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers. Given that elevated FAK expression highly correlates with p53 mutation status in human breast cancer, we set out to investigate the importance of FAK in p53-mediated spontaneous mammary tumour development. METHODS: To directly assess the role of FAK, we generated mice with conditional inactivation of FAK and p53. We generated female p53(lox/lox)/FAK(+/+)/WapCre, p53(lox/lox)/FAK(flox/+)/WapCre and p53(lox/lox)/FAK(flox/-)/WapCre mice, and mice with WapCre-mediated conditional expression of p53(R270H), the mouse equivalent of human p53(R273H) hot spot mutation, together with conditional deletion of FAK, P53(R270H/+)/FAK(lox/+)/WapCre and p53(R270H/+)/FAK(flox/-)/WapCre mice. All mice were subjected to one pregnancy to induce WapCre-mediated deletion of p53 or expression of p53 R270H, and Fak genes flanked by two loxP sites, and subsequently followed the development of mammary tumours. RESULTS: Using this approach, we show that FAK is important for p53-induced mammary tumour development. In addition, mice with the mammary gland-specific conditional expression of p53 point mutation R270H, the mouse equivalent to human R273H, in combination with conditional deletion of Fak showed reduced incidence of p53(R270H)-induced mammary tumours. In both models these effects of FAK were related to reduced proliferation in preneoplastic lesions in the mammary gland ductal structures. CONCLUSIONS: Mammary gland-specific ablation of FAK hampers p53-regulated spontaneous mammary tumour formation. Focal adhesion kinase deletion reduced proliferative capacity of p53 null and p53(R270H) mammary epithelial cells but did not lead to increased apoptosis in vivo. Our data identify FAK as an important regulator in mammary epithelial cell proliferation in p53-mediated and p53(R270H)-induced mammary tumour development.

Project description: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.

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Inhibition of Estrogen Signaling Reduces the Incidence of BRCA1-associated Mammary Tumor Formation.

Publications

Inhibition of Estrogen Signaling Reduces the Incidence of <i>BRCA1</i>-associated Mammary Tumor Formation.

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