Genetic Alterations and Oncogenic Pathways Associated with Breast Cancer Subtypes

Abstract

Breast cancers can be divided into subtypes with important implications for prognosis and treatment. We set out to characterize the genetic alterations observed in different breast cancer subtypes and to identify specific candidate genes and pathways associated with subtype biology. mRNA expression levels of estrogen receptor, progesterone receptor, and HER2 were shown to predict marker status determined by immunohistochemistry and to be effective at assigning samples to subtypes. HER2 + cancers were shown to have the greatest frequency of high-level amplification (independent of the ERBB2 amplicon itself), but triple-negative cancers had the highest overall frequencies of copy gain. Triple-negative cancers also were shown to have more frequent loss of phosphatase and tensin homologue and mutation of RB1, which may contribute to genomic instability. We identified and validated seven regions of copy number alteration associated with different subtypes, and used integrative bioinformatics analysis to identify candidate oncogenes and tumor suppressors, including ERBB2, GRB7, MYST2, PPM1D, CCND1, HDAC2, FOXA1, and RASA1. We tested the candidate oncogene MYST2 and showed that it enhances the anchorage-independent growth of breast cancer cells. The genome-wide and region-specific differences between subtypes suggest the differential activation of oncogenic pathways. (Mol Cancer Res 2009;7(4):511-22)

PIK3CAmutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer

“…5C), the cell line with the highest value of the PIK3CA-GS-the lowest mTORC1 output-was the most rapamycin resistant (ZR751). Of note, the PIK3CA-GS was able to discriminate PIK3CA mutation in status in cell lines using publicly available data (30). However, in cell lines the signature was significantly predictive but in the reverse direction compared with human PIK3CA mt ER+ BCs (AUC = 0.9; P = 0.008; Fig.…”

“…The ER+/ HER2− low (L) and high (H) proliferative subgroups were defined as described in Loi et al (16,27), similar to the Luminal A and B subtypes described by Perou et al (15) BC Cell Lines. The dataset described in Hu et al (30) was used to evaluate the PIK3CA-GS's ability as a continuous variable to predict mutation status in ER+ (luminal) cell lines.…”

The role of S6K1 in ER-positive breast cancer

“…Targeting S6K1 may be an advantageous strategy based on the following data. First, 17q23 amplification strongly correlates with ER-positive status 76 and is one of the most frequent aberrations in ER-positive invasive ductal carcinoma. 77 Similarly, many other common mutations in breast cancer leading to aberrant expression and activation in IGF-1R, ErbB2, FGFR, PIK3CA, PTEN and Akt1/2 result in S6K1 hyperactivation.…”

Comprehensive Expression Analysis Suggests Functional Overlapping of Human FOX Transcription Factors in Cancer

“…Nine FOX genes (2 up-regulated and 7 down-regulated) were differentially expressed in breast cancer. For example, FOXA1 (Schneider et al, 2006;Hu et al, 2009), and FOXM1 (Curtis et al, 2012) were upregulated expression in breast cancer, which play an important roles in breast cancer. In addition, eighteen FOX genes (5 up-regulated and 13 down-regulated) were found to be differentially expressed in oral squamous cell carcinoma.…”

“…Among them, FOXA1 is upregulated in estrogen receptor (ER)-positive breast cancer (Schneider et al, 2006) and FOXA1 point mutations also occur in prostate cancer (Grasso et al, 2012). Overexpression of FOXA1 is associated with estrogen receptor (ER)-positive breast cancer (Hu et al, 2009), lung cancer, esophageal The conserved motifs in full length human FOX proteins. The motifs were identified using Multiple Expectation Maximization for Motif Elicitation (MEME) program version 4.6.1 with default parameters and the maximum number of motifs to find was set to 12…”