Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

Jones, Laundette P.; Tilli, Maddalena T.; Assefnia, Shahin; Torre, Kathleen M.; Halama, Ewa D.; Parrish, Angela R.; Rosen, Eliot M.; Furth, Priscilla A.

doi:10.1038/sj.onc.1210674

Cited by 63 publications

(67 citation statements)

References 40 publications

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“…Selective disruption of Brca1 in the mammary glands of Brca1 f/f:MMTV-Cre mutant mice leads to impaired TEB differentiation upon an exposure to estradiol and progesterone [37], and abberant ductal development during pregnancy, lactation and involution [38]. Overexpression of this tumor suppressor, in turn, stimulates lobulo-alveolar development [13], indicating increased epithelial differentiation.…”

Section: Discussionmentioning

confidence: 99%

Prepubertal physical activity up-regulates estrogen receptor β, BRCA1 and p53 mRNA expression in the rat mammary gland

Wang

Westerlind

et al. 2008

Breast Cancer Res Treat

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Findings in BRCA1 mutation carriers suggest that physical activity, particularly during childhood, may be linked to a reduced risk of developing breast cancer. We investigated whether physical activity at puberty alters the expression of BRCA1 and two other tumor suppressor genes-p53 and estrogen receptor (ER)-β-in rats. In addition, the effects on ER-α expression, mammary proliferation and functional epithelial differentiation were investigated as markers of altered mammary cancer risk in rats exposed to regular physical activity at puberty. Female Sprague Dawley rat pups were randomized to voluntary exercise, sham-exercise control and nonmanipulated control groups. Treadmill training (20-25 m/min, 15% grade, 30 min/day, 5 days/ week) started on postnatal day 14 and continued through day 32. Third thoracic mammary glands © Springer Science+Business Media, LLC. 2008 Correspondence to: L Hilakivi-Clarke, clarkel@georgetown.edu. Authors' contributions The work described in the manuscript was designed to test a hypothesis proposed by Dr. Leena HilakiviClarke who provided overall direction for the study. Drs. Kim Westerlind and Robert Strange performed the animal study and provided tissues for the analysis, Dr. Mingyue Wang did most of the gene and protein expression experiments, together with Drs. Bin Yu, Galam Khan and Dipti Patil. Graduate student Kelly Boeneman processed the mammary glands and performed morphological assessment. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript (n = 5 per group and age) were obtained at days 32, 48 and 100 and assessed for changes in morphology through wholemounts, and at 100 days cell proliferation by using Ki67 staining, protein levels of ER-α and ER-β by immunohistochemistry, and mRNA expression levels of BRCA1, p53, ER-α and ER-β by real-time PCR. Mammary glands of rats exposed to exercise during puberty contained fewer terminal end buds (TEBs) and a higher number of differentiated alveolar buds and lobules than the sham controls. However, cell proliferation was not significantly altered among the groups. ER-α protein levels were significantly reduced, while ER-βlevels were increased in the mammary ducts and lobular epithelial structures of 100-day old rays which were voluntarily exercised at puberty, compared to sham controls. ER-β BRCA1 and p53 mRNA levels were significantly higher in the mammary glands of 100-day-old exercised versus sham control rats. Pubertal physical activity reduced mammary epithelial targets for neoplastic transformation through epithelial differentiation and it also up-regulated tumor suppressor genes BRCA1, p53 and ER-β and reduced ER-α/ER-β ratio in the mammary gland. It remains to be determined whether the up-regulation of BRCA1, and perhaps p53, explains the protective effect of childhood physical activity against breast cancer in women who carry a germline mutation in one of the BRCA1 alleles.

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Section: Discussionmentioning

confidence: 99%

Prepubertal physical activity up-regulates estrogen receptor β, BRCA1 and p53 mRNA expression in the rat mammary gland

Wang

Westerlind

et al. 2008

Breast Cancer Res Treat

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“…The percentage of ER-positive proliferating cells was significantly increased in all of the in situ proliferations examined, such as ductal carcinoma in situ (DCIS), which correlated positively with the risk of developing breast cancer [16]. Increased ERa expression may be the very earliest change occurring in the tumorigenesis process [17,18] as reported at the very earliest stage of ductal hyperplasia and with increasing atypia in atypical ductal hyperplasias and in ductal carcinoma in situ (DCIS) of low and intermediate nuclear grade [19][20][21].…”

Section: Introductionmentioning

confidence: 94%

Overexpression of ligase defective E6-associated protein, E6-AP, results in mammary tumorigenesis

Ramamoorthy

Tufail

Hokayem

et al. 2011

Breast Cancer Res Treat

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E6-associated protein (E6-AP) is a dual function protein. It acts as an E3 ubiquitin-protein ligase enzyme and coactivator of steroid hormone receptors such as estrogen (ERα) and progesterone (PR) receptors. It promotes the degradation of ERα and PR through the ubiquitin-proteasome pathway. Furthermore, it has been shown that the levels of E6-AP are inversely associated with that of ERα in human breast tumors. But the role of wild-type human E6-AP and its ubiquitin-protein ligase activity in mammary tumorigenesis is still unknown. To investigate this role, the authors utilized transgenic mice lines that specifically overexpress either the wild-type human E6-AP (E6-AP(WT)) or the ubiquitin-protein ligase defective E6-AP that contains C833S mutation (E6-AP(C833S)) in the mammary gland. To further substantiate the role of E6-AP in the development of breast tumorigenesis, it was also examined the expression of E6-AP in a large cohort of human breast cancer samples. The transgenic mice that overexpress wild-type E6-AP (E6-AP(WT)) fail to develop mammary tumors. Unlike the E6-AP(WT) mice, the E6-AP(C833S) mice that overexpress ubiquitin-protein ligase defective E6-AP protein develop mammary hyperplasia with a median latency of 18 months. These observations suggest that the inactivation of the ubiquitin-protein ligase function of E6-AP is sufficient to initiate the process of mammary tumor development. Furthermore, the data also suggests that E6-AP exerts its effects on target cells by modulating the protein levels and functions of ERα and PR. In addition, it was found in human breast cancer patients that the level of E6-AP is decreased in invasive breast tumors compared to normal breast tissue. Moreover, the authors also show that the survival patterns for E6-AP negative patients were worse compared to E6-AP positive patients. Taken together, these data suggests that E6-AP may act as a tumor suppressor in breast.

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“…In the representative experiment presented here, a critical question was to determine if changes in expression levels of genes known to impact mammary cancer risk (Brca1, Tp53,and estrogen receptor 1 (Esr1) 1 ) altered the number of hours between cell divisions (cell lifetime) or impacted the patterns of division (symmetric versus asymmetric) in non-cancerous primary mammary epithelial cells. To accomplish this, individual cell fate maps (trees) were generated using TTT.…”

Section: Representative Resultsmentioning

confidence: 99%

“…For example, genetically engineered mice have shown that the combination of three factors: loss of the full-length breast cancer 1, early onset (Brca1) gene in mammary epithelial cells, tumor protein p53 (Tp53) germ-line haploinsufficiency, and mammary epithelial cell targeted up-regulated Estrogen receptor alpha (ERa) expression results in the development of mammary cancer in 100% of Brca1 haploinsufficiency (<5%). 1 1. Generate primary cultures of preneoplastic mammary epithelial cells from mammary glands of genetically engineered and control wild-type mice.…”

Section: Introductionmentioning

confidence: 99%

Time-lapse Imaging of Primary Preneoplastic Mammary Epithelial Cells Derived from Genetically Engineered Mouse Models of Breast Cancer

Nakles

Millman

Cabrera

et al. 2013

JoVE

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Time-lapse imaging can be used to compare behavior of cultured primary preneoplastic mammary epithelial cells derived from different genetically engineered mouse models of breast cancer. For example, time between cell divisions (cell lifetimes), apoptotic cell numbers, evolution of morphological changes, and mechanism of colony formation can be quantified and compared in cells carrying specific genetic lesions. Primary mammary epithelial cell cultures are generated from mammary glands without palpable tumor. Glands are carefully resected with clear separation from adjacent muscle, lymph nodes are removed, and single-cell suspensions of enriched mammary epithelial cells are generated by mincing mammary tissue followed by enzymatic dissociation and filtration. Single-cell suspensions are plated and placed directly under a microscope within an incubator chamber for live-cell imaging. Sixteen 650 μm x 700 μm fields in a 4x4 configuration from each well of a 6-well plate are imaged every 15 min for 5 days. Time-lapse images are examined directly to measure cellular behaviors that can include mechanism and frequency of cell colony formation within the first 24 hr of plating the cells (aggregation versus cell proliferation), incidence of apoptosis, and phasing of morphological changes. Single-cell tracking is used to generate cell fate maps for measurement of individual cell lifetimes and investigation of cell division patterns. Quantitative data are statistically analyzed to assess for significant differences in behavior correlated with specific genetic lesions. Video LinkThe video component of this article can be found at

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Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

Cited by 63 publications

References 40 publications

Prepubertal physical activity up-regulates estrogen receptor β, BRCA1 and p53 mRNA expression in the rat mammary gland

Prepubertal physical activity up-regulates estrogen receptor β, BRCA1 and p53 mRNA expression in the rat mammary gland

Overexpression of ligase defective E6-associated protein, E6-AP, results in mammary tumorigenesis

Time-lapse Imaging of Primary Preneoplastic Mammary Epithelial Cells Derived from Genetically Engineered Mouse Models of Breast Cancer

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