Laminin-rich extracellular matrix association with mammary epithelial cells suppresses Brca1 expression

O'Connell, F C; Martin, Finian

doi:10.1038/sj.cdd.4400647

Cited by 15 publications

(19 citation statements)

References 71 publications

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“…Wholemounting, carmine staining and analysis was carried out essentially as described by O'Connell and Martin (2000). For LacZ staining, glands or embryos were removed whole to PBS/ MgCl 2 (2 mM) on ice and subsequently stained using a LacZ reporter-staining kit (Invivogen, San Diego, CA).…”

Section: Wholemount Analysismentioning

confidence: 99%

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CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis

et al. 2005

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Section: Wholemount Analysismentioning

confidence: 99%

“…Additional information on quality control and 18S normalization can be found in Supplementary data 4. Semi-quantitative RT-PCR was carried out as previously described (O'Connell and Martin, 2000).…”

Section: Rt-pcr and Western Analysismentioning

confidence: 99%

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis

et al. 2005

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“…2 The mouse GAPDH, ␤-casein, and WAP primers were as reported previously (47). The other primers used are as follows: clusterin, sense 5Ј-GTC CTT CCA GTC GAA GAT GC-3Ј, and antisense 5Ј-TCC TGC GGT ATT CCT GTA GC-3Ј; IGFBP-5, sense 5Ј-CCG AGG TAA AGC CAG ACT CC-3Ј, and antisense 5Ј-CAT CCA CGT ACT CCA TGC C-3Ј; and TGF-␤1, sense 5Ј-CAA CAA TTC CTG GCG TTA CC-3Ј, and antisense 5Ј-GTT GGT TGT AGA GGG CAA GG-3Ј.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was isolated from cultured cells using TRIZOL Reagent (Invitrogen) according to the manufacturer's instructions. Reverse transcription and limiting cycle PCR were carried out essentially as described previously (47). Depending on the abundance of the transcript being detected, 15-40 PCR cycles were carried out.…”

Section: Methodsmentioning

confidence: 99%

Transcription Factor NFIC Undergoes N-Glycosylation during Early Mammary Gland Involution

Kane

Murtagh

Finlay

et al. 2002

Journal of Biological Chemistry

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Expression of a 74-kDa nuclear factor I (NFI) protein is triggered in early involution in the mouse mammary gland, and its expression correlates with enhanced occupation of a twin (NFI) binding element in the clusterin promoter, a gene whose transcription is induced at this time (Furlong, E. E., Keon, N. K., Thornton, F. D., Rein, T., and Martin, F. (1996) J. Biol. Chem. 271, 29688 -29697). We now identify this 74-kDa NFI as an NFIC isoform based on its interaction in Western analysis with two NFIC-specific antibodies. A transition from the expression of a 49-kDa NFIC in lactation to the expression of the 74-kDa NFIC in early involution is demonstrated. We show that the 74-kDa NFIC binds specifically to concanavalin A (ConA) and that this binding can be reversed by the specific ConA ligands, methyl ␣-D-mannopyranoside and methyl ␣-D-glucopyranoside. In addition, its apparent molecular size was reduced to ϳ63 kDa by treatment with the peptide N-glycosidase. The 49-kDa lactation-associated NFIC did not bind ConA nor was it affected by peptide N-glycosidase. Tunicamycin, a specific inhibitor of N-glycosylation, blocked formation of the 74-kDa NFI in involuting mouse mammary gland in vivo when delivered from implanted Elvax depot pellets. Finally, the production of the ConA binding activity could be reiterated in "mammospheres" formed from primary mouse mammary epithelial cells associated with a laminin-rich extracellular matrix. Synthesis of the 74-kDa NFIC was also inhibited in this setting by tunicamycin. Thus, involution triggers the production of an NFIC isoform that is post-translationally modified by N-glycosylation. We further show, by using quantitative competitive reverse transcriptase-PCR, that there is increased expression of the major mouse mammary NFIC mRNA transcript, mNFIC2, in early involution, suggesting that the involution-associated change in NFIC expression also has a transcriptional contribution.

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“…The strong effect of collagen type IV on BRCA1 mRNA levels implicates ßi, ai and ct2 integrins (collagen receptors) in addition to 0^4 (laminin receptor). Recently, it was implied that Matrigel matrix suppressed expression of BRCA1 in normal breast epithelial cells (49). These authors attributed this suppressive effect of Matrigel to laminin.…”

Section: Effect Of Ecm Onmentioning

confidence: 99%

Biological Function of BRCA1 and Its Regulation by the Extracellular Matrix and PTEN in Breast Cancer

Miralem¹,

Avraham²

2002

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Beth Israel Deaconess Medical Center Boston, Massachusetts 02215 email tmiralem@caregroup.harvard.edu A high incidence of familial breast and ovarian cancer is associated with inactivation of BRCA1. We demonstrated previously that HRG induced the phosphorylation of BRCA1, which was mediated by the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Since both extracellular matrix (ECM) and PTEN can modulate PBK/Akt pathway we hypothesized that ECM and PTEN may affect the expression and phosphorylation of BRCA1. To test this we wanted: 1) To determine the effect of ECM/integrins on BRCA1 expression, phosphorylation and nuclear translocation. 2) To characterize biological functions of BRCA1 in breast cancer cells. 3) To determine the effect of PTEN on BRCA1 phosphorylation. Both cell proliferation and BRCA1 phosphorylation were enhanced in T47D cells seeded on laminin after treatment with heregulin (HRG). The enhanced BRCA1 phosphorylation on laminin was mediated through a 6 ß4 integrins. Overexpression of BRCA1 inhibited HRG-dependent DNA synthesis in breast cancer cells. HRG suppressed BRCA1 expression through protein degradation, which required both calpain and proteosome. ECM suppressed BRCA1 mRNA expression through its C-terminus, while forced expression of PTEN inhibited HRG-dependent activation of Akt. Taken together these findings show that while BRCA1 suppresses HRG-dependent DNA synthesis, ECM and/or HRG can regulate BRCA1 expression and phosphorylation. Experiments with PTEN indicated that this phosphatase could affect phosphorylation of BRCA1. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U14. Subject Terms (keywords previously assigned to proposal abstract or terms which apply to this award)BRCA1, heregulin, extracellular matrix, PTEN, phosphorylation Manuscript Submitted for publication to MCB Appendix C MIRALEM, Tihomir, P.I. 1 Award -DAMD17-00-1-0152 TNTRODUCTION BRCA1 is tumor suppressor gene whose inactivation is associated with a high incidence of familial breast and ovarian cancer [1]. The BRCA1 protein can be phosphorylated by heregulin through phosphatidyl inositol-3 kinase (PI3K)/AKT-dependent pathway [2] and cell cycle-dependent manner [3]. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a tumor suppressor gene located at 10q23 [4]. Deletions in 10q22-25 occur in multiple tumor types and PTEN is one of the most common targe...

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Laminin-rich extracellular matrix association with mammary epithelial cells suppresses Brca1 expression

Cited by 15 publications

References 71 publications

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis

Transcription Factor NFIC Undergoes N-Glycosylation during Early Mammary Gland Involution

Biological Function of BRCA1 and Its Regulation by the Extracellular Matrix and PTEN in Breast Cancer

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