Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver

Abstract

Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures. We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer. Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can drive breast cancer. This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations.

Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients

“…Indeed, 28% of human breast tumors have deletions or loss-of-function mutations in NF1, which codes for a Ras GTPase activating protein (Gap; ref. 1). Other tumors show reduced expression of RASAL2, a distinct RasGap gene.…”

The Chromatin Remodeling ComponentArid1aIs a Suppressor of Spontaneous Mammary Tumors in Mice

“…Most females homozygous for the Chaos3 mutation congenic in the C3HeB/FeJ strain background (C3H-Chaos3) develop spontaneous mammary tumors (MTs) with an average latency of 12 months (Shima et al 2007). Array Comparative Genomic Hybridization (aCGH) analyses of nine C3H-Chaos3 MTs revealed interstitial deletions common to a small number of chromosomal regions (Wallace et al 2012). Almost all tumors were missing both copies of Nf1, a tumor suppressor that functions as negative regulator of Ras, but positive for Trp53 (Wallace et al 2014).…”

Male breast cancer with neurofibromatosis- a rare presentation

“…Concerning the association between NF1 and breast cancer, only a few cases have been reported. 9,10 About 28% of sporadic breast cancers are missing atleast one copy of NF 1 gene, either due to deletion or mutation. 11 The first cases describing the association of NF 1 with breast cancer were reported in the 1970's by Brasfield and Das Gupta.…”

“…3,4 Male Breast Cancer is a rare disease and accounts for less than 1% of all breast cancers. 5 Here we are reporting a case of male cancer with neurofibromatosis.…”