Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations.
BACKGROUND
Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers.


METHODS
We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data.


RESULTS
Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma.


CONCLUSIONS
These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.
Banneau
Guillaume
G
INSERM U916, Université de Bordeaux, Institut Bergonié, 229 cours de l'Argonne, 33000, Bordeaux, France.
Guedj
Mickaël
M
MacGrogan
Gaëtan
G
de Mascarel
Isabelle
I
Velasco
Valerie
V
Schiappa
Renaud
R
Bonadona
Valerie
V
David
Albert
A
Dugast
Catherine
C
Gilbert-Dussardier
Brigitte
B
Ingster
Olivier
O
Vabres
Pierre
P
Caux
Frederic
F
de Reynies
Aurelien
A
Iggo
Richard
R
Sevenet
Nicolas
N
Bonnet
Françoise
F
Longy
Michel
M
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D005723:gamma-Glutamyltransferase; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human