Basal-like breast cancer and the BRCA1 phenotype

Turner, Nicholas C.; Reis‐Filho, Jorge S.

doi:10.1038/sj.onc.1209876

Cited by 417 publications

(365 citation statements)

References 104 publications

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“…[1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 .…”

Section: Introductionmentioning

confidence: 99%

“…Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype [3][4][5] ; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers.…”

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confidence: 99%

“…Indeed, recurrent fusions between TMPRSS2 and ETS family transcription factor genes have been identified in prostate carcinoma by a systems biology approach 9 , and they suggest that oncogenic gene rearrangements may be common in epithelial neoplasia. Global gene expression profiling studies of breast carcinoma have delineated several molecular subtypes that have distinct pathological and clinical characteristics [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis [2][3][4][5] .…”

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confidence: 99%

“…Global gene expression profiling studies of breast carcinoma have delineated several molecular subtypes that have distinct pathological and clinical characteristics [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis [2][3][4][5] . The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs.…”

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confidence: 99%

“…The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs. 1,3,5 ). In addition to having characteristic cytokeratin expression, BBCs are highly proliferative, poorly differentiated and genomically unstable, and they pose clinical challenges because they rarely express the three most common therapeutically targeted 'Achilles' heels' of breast cancer: the estrogen receptor (ER), progesterone receptor and HER2 receptor (refs.…”

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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis [1][2][3] . Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype [3][4][5] ; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent Correspondence should be addressed to R.P. (rep15@columbia.edu). 14 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS L.H.S., S.K.G.-S., R.P. and Å.B conceived and designed the study; L.H.S., S.K.G.-S., J.S., G.J., K.H., S.K., J.V.-C., H.O., T.S., L.M., S.P.E., H.H., R.P. and Å.B. collected the samples; L.H.S., K.L., M.J., L.M., T.L., M.S., J.I. and H.H. performed and analyzed immunohistochemistry experiments; L.H.S. and C.P. designed and performed methylation analyses; L.H.S., C.P., M.M. and K.H. performed nucleotide sequencing experiments; L.H.S., J.S., G.J. and K.H. performed and analyzed aCGH experiments; L.H.S., M.M.P., S.S. and V.V.V.S.M. designed and performed FISH experiments; L.H.S., S.K.G.-S. and M.K. performed statistical analyses; R.P. and Å.B. supervised the study; and L.H.S. wrote the paper with assistance from R.P. and Å.B. and input from all coauthors.Note: Supplementary information is available on the Nature Genetics website. [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 . The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs. 1,3,5 ). In addition to having characteristic cytokeratin expression, BBCs are highly proliferative, poorly differentiated and genomically unstable, and they pose clinical challenges because they rarely express the three most common therapeutically targeted 'Achilles' heels' of breast cancer: the estrogen receptor (ER), progesterone receptor and HER2 receptor (refs. 1,3,5,7 ).Intriguingly, breast tumors initiated by an inherited mutation of BRCA1 are nearly always basal-like 3,5 . BRCA1 dysfunction is thought to be tumorigenic primarily owing to defective BRCA1-dependent DSB repair, which precipitates an accumulation of secondary mutations 10 ; however, only general genomic patterns at relatively low resolution have been described (reviewed in ref. 5 ). Despite these advances in delineating BBC, the molecu...

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“…[1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 .…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

Zhang,

Ye,

Bernhardt

et al. 2024

JAMA Netw Open

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ImportanceIn young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown.ObjectiveTo determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs.Design, Setting, and ParticipantsThis prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023.ExposureTime between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years.Main Outcomes and MeasuresThe primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status.ResultsAmong 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]).Conclusions and RelevanceThese findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

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Optochemische Steuerung biologischer Vorgänge in Zellen und Tieren

et al. 2018

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This article is protected by copyright. All rights reserved optochemical control of biology. In contrast to excellent previous reviews that focus on the chemistry of controlling biological function with light, [1] this review focuses on manipulation of cell and animal biology using photochemical approaches. Purely optogenetic approaches, not utilizing chemical operations, have been reviewed elsewhere. [2] 2. Optical control of small molecules Small molecule probes have been essential tools to perturb and control cellular processes, thereby providing an understanding of detailed biological function. Optical control of small molecule function provides an extra layer of precision to the molecular toolbox by enabling temporal and spatial control with high resolution, as discussed in the examples below. Small molecule protein dimerizers, inhibitors, metabolites, and metal ions have all been rendered lightresponsive through the chemical installation of caging groups and have been applied to the investigation of living systems. In contrast to photocaged nucleic acids, peptides, and proteins, small molecules have the added benefits of being synthetically more accessible and capable of being readily delivered into cells and animals. 2.1. Optical activation of rapamycin induced dimerization Chemical inducers of dimerization (CIDs) are prominent tools for chemical biologists to place biological processes under conditional control. [3] The most commonly utilized CID is rapamycin, which binds to FK506 binding protein (FKBP) and the FKBP-rapamycin binding domain of mTOR (FRB), forming a ternary complex. Due to the small size of FKBP and FRB, these domains have been fused to numerous proteins and subsequent heterodimerization was induced by rapamycin. Processes that have been placed under rapamycin control include Golgi/endoplasmic reticulum association to study mitosis, [4] phosphoinositide control of endocytic trafficking, [5] and inactivation of proteins by rerouting them to the mitochondria. [6] Caged rapamycin analogs allow for placement of these processes under optical control in order to enhance temporal and spatial resolution. The photocaged rapamycin analog 1 was generated through installation of a nitrobenzyl caging group at the C-40 position (Figure 1a). [7] When applied to cells, 1 still induced FKBP-FRB dimerization, indicating that the caging group alone wasn't sufficient to abrogate protein-small molecule interaction, which is consistent with previous modifications at C-40. [8] However, work by the Hahn lab had shown that a truncated FKBP, termed iFKBP, [9] exhibited increased flexibility in the loop that interacts with the C-40 position of rapamycin. This flexibility increased contacts for interaction with 1 and resulted in a distorted binding conformation that prevented formation of the ternary complex consisting of iFKBP, FRB, and 1. This system was then applied to the optical activation of FAK (focal adhesion kinase), using an engineered iFKBP-FAK fusion which rendered the kinase inactive until UV irradiation...

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Basal-like breast cancer and the BRCA1 phenotype

Cited by 417 publications

References 104 publications

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

Optochemische Steuerung biologischer Vorgänge in Zellen und Tieren

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