Background
Methods
Human breast cancer samples
Variable |
n
| % | Total |
---|---|---|---|
Breast tumors | 116 | 100.0 % | 116 |
Median age (range) | 53 years | (30–89) | |
ER+ | 82 | 70.7 % | 116 |
ER– | 34 | 29.3 % | |
PgR+ | 71 | 61.2 % | 116 |
PgR– | 45 | 38.8 % | |
Size <20 | 36 | 31.3 % | 115 |
20–49 | 64 | 55.7 % | |
50+ | 15 | 13.0 % | |
Grade 1 | 8 | 7.0 % | 115 |
Grade 2 | 32 | 27.8 % | |
Grade 3 | 75 | 65.2 % | |
Node+ | 56 | 53.3 % | 105 |
Node– | 49 | 46.7 % | |
HER2+ | 23 | 20.4 % | 113 |
HER2– | 90 | 79.6 % | |
Ki67 IHC+ | 35 | 38.0 % | 92 |
Ki67 IHC– | 57 | 62.0 % | |
S–phase ≤6 % | 31 | 33.3 % | 93 |
S–phase >6 %,<10 % | 17 | 18.3 % | |
S–phase ≥10 % | 45 | 48.4 % | |
CK5/14 IHC+ | 19 | 17.4 % | 109 |
CK5/14 IHC– | 90 | 82.6 % | |
p53 mut | 44 | 38.3 % | 115 |
p53 wt | 71 | 61.7 % | |
EGFR IHC+ | 27 | 24.1 % | 112 |
EGFR IHC– | 85 | 75.9 % | |
PTEN abrogated (PTEN IHC- or mut) | 26 | 24.3 % | 107 |
PTEN norm | 81 | 75.7 % | |
PTEN IHC– | 25 | 23.4 % | 107 |
PTEN IHC+ | 82 | 76.6 % | |
PTEN mut | 4 | 3.6 % | 112 |
PTEN wt | 108 | 96.4 % | |
PIK3CA mut | 29 | 25.0 % | 116 |
PIK3CA wt | 87 | 75.0 % | |
INPP4B mRNA low | 20 | 21.3 % | 94 |
INPP4B mRNA norm | 74 | 78.7 % | |
Any PTEN/PI3K/INPP4B | 64 | 64.0 % | 100 |
None PTEN/PI3K/INPP4B | 36 | 36.0 % | |
Any PTEN/PI3K/INPP4B/EGFR/HER2 | 80 | 75.5 % | 106 |
None PTEN/PI3K/INPP4B/EGFR/HER2 | 26 | 24.5 % |
Tissue microarray construction
Immunohistochemistry and Western blotting
HER2 amplification
PCR and sequence analysis
Gene expression profiling
Cell viability and apoptosis assays
Animal studies
Data visualization and statistical analysis
Results
Distribution of biomarker lesions
PTEN/PI3K pathway-related tumor clusters
Associations between pathway lesions
PTEN mut | PTEN wt | n | p | HER2+ | HER2- | n | p | EGFR+ | EGFR- | n | p | PIK3CA mut | PIK3CA wt | n | p | INPP4B low | INPP4B high | n | p | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PTEN IHC- | 3 | 20 | 103 |
0.010
| 2 | 23 | 107 | 0.117 | 14 | 11 | 107 |
<0.0001
| 1 | 24 | 107 |
0.012
| 6 | 11 | 85 | 0.111 |
PTEN IHC+ | 1 | 79 | 18 | 64 | 12 | 70 | 23 | 59 | 12 | 56 | ||||||||||
PTEN abrogation | 2 | 24 | 107 | 0.098 | 14 | 12 | 107 |
<0.0001
| 2 | 24 | 107 | 0.072 | 6 | 12 | 85 | 0.155 | ||||
PTEN normal | 18 | 63 | 12 | 69 | 22 | 59 | 12 | 55 | ||||||||||||
HER2+ | 8 | 14 | 110 | 0.150 | 6 | 17 | 113 | 0.871 | 3 | 15 | 91 | 0.624 | ||||||||
HER2- | 19 | 69 | 22 | 68 | 16 | 57 | ||||||||||||||
EGFR+ | 5 | 22 | 112 | 0.436 | 8 | 12 | 90 |
0.019
| ||||||||||||
EGFR- | 22 | 63 | 11 | 59 | ||||||||||||||||
PIK3CA mut | 4 | 24 | 94 | 0.281 | ||||||||||||||||
PIK3CA wt | 16 | 50 |
Pathway lesions and clinicopathological variables
ER+ | ER– |
n
|
P
| PgR+ | PgR – |
n
|
P
| p53 mut | p53 wt |
n
|
P
| CK5/14 + | CK5/14 – |
n
|
P
| Grade 1 | Grade 2 | Grade 3 |
n
|
P
| <20 mm | 20–49 mm | 50 mm+ |
n
|
P
| Node+ | Node – |
n
|
P
| S–phase ≤6 % | S–phase 6-10 % | S–phase ≥10 % |
n
|
P
| Basal-like | HER2 | Normal-like | LumA | LumB |
n
|
P
| |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PTEN IHC– | 11 | 14 | 107 |
0.0007
| 8 | 17 | 107 |
0.0003
| 15 | 9 | 106 |
0.006
| 11 | 13 | 106 |
<0.0001
| 0 | 2 | 23 | 106 |
0.002
| 3 | 14 | 8 | 107 |
0.002
| 14 | 8 | 97 | 0.392 | 4 | 1 | 13 | 85 | 0.062 | 11 | 2 | 2 | 0 | 2 | 86 |
0.0003
|
PTEN IHC+ | 65 | 17 | 59 | 23 | 26 | 56 | 7 | 75 | 8 | 27 | 46 | 28 | 47 | 7 | 40 | 35 | 24 | 15 | 28 | 11 | 6 | 8 | 31 | 13 | ||||||||||||||||||
PTEN mut | 2 | 2 | 112 | 0.334 | 2 | 2 | 112 | 0.600 | 3 | 1 | 112 | 0.115 | 2 | 2 | 105 | 0.061 | 0 | 0 | 4 | 111 | 0.166 | 0 | 3 | 1 | 111 | 0.175 | 2 | 2 | 101 | 0.855 | 1 | 0 | 2 | 91 | 0.708 | 3 | 0 | 0 | 0 | 0 | 94 |
0.048
|
PTEN wt | 78 | 30 | 68 | 40 | 39 | 69 | 15 | 86 | 8 | 31 | 68 | 35 | 58 | 14 | 53 | 44 | 30 | 16 | 42 | 20 | 10 | 10 | 34 | 17 | ||||||||||||||||||
PTEN abrogated | 12 | 14 | 107 |
0.001
| 9 | 17 | 107 |
0.0007
| 16 | 9 | 106 |
0.003
| 11 | 14 | 106 |
<0.0001
| 0 | 2 | 24 | 106 |
0.0012
| 3 | 14 | 9 | 107 |
0.0005
| 15 | 8 | 97 | 0.291 | 5 | 1 | 13 | 85 | 0.135 | 12 | 2 | 2 | 0 | 2 | 86 |
<0.0001
|
PTEN normal | 64 | 17 | 58 | 23 | 25 | 56 | 7 | 74 | 8 | 27 | 45 | 28 | 47 | 6 | 39 | 35 | 23 | 15 | 28 | 10 | 6 | 8 | 31 | 13 | ||||||||||||||||||
HER2+ | 13 | 10 | 113 | 0.092 | 13 | 10 | 113 | 0.548 | 13 | 10 | 112 | 0.058 | 3 | 18 | 108 | 0.740 | 1 | 7 | 15 | 112 | 0.806 | 7 | 13 | 3 | 113 | 0.979 | 13 | 8 | 103 | 0.437 | 3 | 3 | 10 | 90 | 0.177 | 3 | 7 | 3 | 2 | 3 | 92 |
0.0003
|
HER2– | 67 | 23 | 57 | 33 | 31 | 58 | 15 | 72 | 7 | 24 | 58 | 28 | 50 | 12 | 43 | 39 | 26 | 14 | 34 | 19 | 3 | 8 | 31 | 13 | ||||||||||||||||||
EGFR+ | 4 | 23 | 112 |
<0.0001
| 5 | 22 | 112 |
<0.0001
| 19 | 8 | 111 |
<0.0001
| 15 | 11 | 109 |
<0.0001
| 0 | 2 | 25 | 111 |
0.0008
| 6 | 16 | 5 | 112 | 0.216 | 13 | 9 | 102 | 0.583 | 5 | 3 | 14 | 89 | 0.112 | 16 | 3 | 1 | 0 | 0 | 91 |
<0.0001
|
EGFR– | 74 | 11 | 63 | 22 | 24 | 60 | 4 | 79 | 8 | 29 | 47 | 28 | 47 | 10 | 42 | 38 | 25 | 13 | 29 | 7 | 6 | 10 | 32 | 16 | ||||||||||||||||||
PIK3CA mut | 22 | 7 | 116 | 0.480 | 21 | 8 | 116 | 0.153 | 11 | 18 | 115 | 0.966 | 4 | 22 | 109 | 0.753 | 4 | 10 | 14 | 115 |
0.027
| 10 | 16 | 3 | 115 | 0.568 | 16 | 11 | 105 | 0.474 | 13 | 3 | 9 | 93 |
0.042
| 5 | 3 | 5 | 12 | 3 | 95 | 0.446 |
PIK3CA wt | 60 | 27 | 50 | 37 | 33 | 53 | 15 | 68 | 4 | 22 | 61 | 26 | 48 | 12 | 40 | 38 | 18 | 14 | 36 | 18 | 7 | 6 | 22 | 14 | ||||||||||||||||||
INPP4B low | 10 | 10 | 94 |
0.012
| 12 | 8 | 94 | 0.773 | 10 | 10 | 93 | 0.292 | 6 | 13 | 88 | 0.057 | 3 | 3 | 14 | 94 | 0.954 | 8 | 7 | 5 | 93 | 0.928 | 9 | 10 | 85 | 0.750 | 5 | 6 | 3 | 73 | 0.235 | 11 | 1 | 1 | 7 | 0 | 94 |
0.003
|
INPP4B high | 58 | 16 | 47 | 27 | 27 | 46 | 9 | 60 | 5 | 24 | 45 | 19 | 47 | 7 | 34 | 32 | 20 | 9 | 30 | 12 | 9 | 10 | 26 | 17 | ||||||||||||||||||
Any PTEN/PI3K/INPP4B | 44 | 17 | 95 | 0.434 | 37 | 24 | 95 | 0.333 | 24 | 36 | 94 | 0.305 | 11 | 47 | 89 | 0.467 | 2 | 13 | 45 | 94 |
0.004
| 18 | 34 | 8 | 94 | 0.561 | 27 | 27 | 84 | 0.379 | 20 | 6 | 26 | 78 | 0.594 | 14 | 4 | 6 | 18 | 9 | 83 | 0.892 |
None PTEN/PI3K/INPP4B | 27 | 7 | 24 | 10 | 10 | 24 | 4 | 27 | 5 | 13 | 16 | 8 | 21 | 5 | 18 | 12 | 6 | 8 | 12 | 6 | 2 | 5 | 12 | 7 | ||||||||||||||||||
Any PTEN/PI3K/INPP4B/EGFR/HER2 | 47 | 33 | 106 |
0.0004
| 43 | 37 | 106 |
0.014
| 40 | 39 | 105 |
0.0004
| 19 | 56 | 101 |
0.0044
| 6 | 17 | 56 | 105 | 0.081 | 21 | 47 | 12 | 106 | 0.268 | 40 | 33 | 96 | 0.559 | 23 | 10 | 30 | 84 | 0.319 | 23 | 10 | 9 | 16 | 8 | 92 |
<0.0001
|
None PTEN/PI3K/INPP4B/EGFR/HER2 | 25 | 1 | 21 | 5 | 3 | 23 | 0 | 26 | 2 | 12 | 12 | 9 | 15 | 2 | 11 | 12 | 4 | 6 | 11 | 0 | 0 | 2 | 16 | 8 |