Truncating mutations of RB1CC1 in human breast cancer

Abstract

The protein RB1CC1 (retinoblastoma 1 (RB1)-inducible coiled-coil 1) has been identified as a key regulator of the tumor-suppressor gene RB1 (ref. 1). RB1CC1 is localized in the nucleus and has been proposed to be a transcription factor because of its nuclear localization signal, leucine zipper motif and coiled-coil structure. The gene RB1CC1 is localized to a region of chromosome 8q11 (ref. 2) containing several loci of putative tumor-suppressor genes; however, its role in human cancers remains to be determined. Here we report that 20% (7 of 35) of primary breast cancers examined contained mutations in RB1CC1, including nine large interstitial deletions predicted to yield markedly truncated RB1CC1 proteins. Wildtype RB1CC1 and RB1 were absent or significantly less abundant than normal in the seven cancers with mutations in RB1CC1, but were abundant in cancers without such mutations. In all seven cancers, both RB1CC1 alleles were inactivated; two showed compound heterozygous deletions. Thus, RB1CC1 is frequently mutated in breast cancer and shows characteristics of a classical tumor-suppressor gene.

From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression

“…It is thought to be an activator of the retinoblastoma tumor suppressor gene (19). Inactivation of the retinoblastoma pathway is believed to be a very early genetic event in oncogenesis.…”

“…LOH analysis on the primary PCR products from microdissected tumors and single cells was performed as described (16). Microsatellite markers for RB1CC1 were as published by Chano et al (19). Primer sequences for the microsatellite markers on chromosome 16 were: D16S3095, 5Ј-TATAGTTTGTGTCCCCCGAC and 5Ј-TCAGTTGGAAG-ATGAGTTGG-3Ј; D16S485 5Ј-AGGCAATTTGTTACA-GAGCC-3Ј and 5Ј-AGTAATAATGTACCTGGTACC-3Ј; D16S511, 5Ј-CAGAGGCCTCATTTTCTAACC-3Ј and 5Ј-TGCTACATA A AGAGGGAGGC-3Ј; and D16S505, 5Ј-GGCCCTAAATCCAGTGCTG-3Ј and 5Ј-CTGCCTCCAT-ACGTGGAGG-3Ј.…”

Autophagy: for better or for worse

“…Compound heterozygous deletions Breast cancer [218] Loss-of-heterozyosity UVRAG Mono-allelic deletion Colon cancer [219] Frameshift mutation Colon cancer [220,221] Gastric cancer the BH3 mimetic, obatoclax, abrogates glucocorticoid resistance by promoting Beclin-1-mediated autophagy and inducing necroptotic cell death [158]. In addition, knockdown of transglutaminase 2 (TG2) or Bcl-2, both of which are important autophagy suppressors strongly expressed in many tumors, was shown to induce ACD in cancer cells [194,195].…”

FIP200, a key signaling node to coordinately regulate various cellular processes

“…Overexpression of FIP200 has been shown to upregulate RB1 expression and inhibit cell proliferation in human leukemic cells, such as K562 and Jurkat cells [30]. In addition, RB1 expression correlates with FIP200 expression in the breast cancer cells with FIP200 truncation, suggesting that FIP200 regulation of RB1 expression might play a role in its tumor suppression [31]. Our recent study demonstrated that FIP200 could also inhibit cell proliferation in human breast cancer cells [14].…”

“…It was found that 20% (7 of 35) of primary breast cancers that were screened contain large deletion mutations in FIP200 that are predicted to generate markedly truncated proteins lacking the NLS, the leucine zipper motif and the coiled-coil region [31]. In all seven cases, both FIP200 alleles were inactivated with two primary breast cancers containing compound heterozygous deletions in both alleles and the other five showing loss of heterozygosity (LOH) of FIP200 [31]. Furthermore, LOH of FIP200 was also observed in several primary breast cancer samples in another study [50].…”