Abstract
IntroductionAlthough a substantial proportion of male breast cancers (MBCs) are hereditary, the molecular pathways that are activated are unknown. We therefore examined the frequency and clinicopathological associations of the PIK3CA/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways and their regulatory genes in familial MBC.MethodsHigh resolution melting analysis and confirmatory sequencing was used to determine the presence of somatic mutations in PIK3CA (exon 9 and 20), AKT1 (exon 4), KRAS (exon 2) and BRAF (exon 15) genes in 57 familial MBCs. Further analysis of the PIK3CA/mTOR pathway was performed using immunohistochemistry for the pAKT1, pS6 and p4EBP1 biomarkers.ResultsPIK3CA somatic mutations were identified in 10.5% (6 of 57) of cases; there were no AKT1, KRAS or BRAF somatic mutations. PIK3CA mutations were significantly more frequent in cancers from BRCAX patients (17.2%, 5/29) than BRCA2 (0%, 0/25) carriers (P = 0.030). Two BRCAX patients had an E547K mutation which has only been reported in one female breast cancer previously. PIK3CA mutation was significantly correlated with positive pS6 (83.3% vs. 32.0%, P = 0.024) and negative p4EBP1 (100% vs. 38.0%, P = 0.006) expression, but not pAKT expression. Expression of nuclear p4EBP1 correlated with BRCA2 mutation carrier status (68.0% vs. 38.7%, P = 0.035).ConclusionsSomatic PIK3CA mutation is present in familial male breast cancer but absent in BRCA2 carriers. The presence of two of the extremely rare E547K PIK3CA mutations in our cohort may have specific relevance in MBCs. Further study of PIK3CA in MBCs, and in particular BRCAX patients, may contribute to further establishing the relevance of specific PIK3CA mutations in MBC aetiology and in the identification of particular patient groups most likely to benefit from therapeutic targeting with the novel PIK3CA inhibitors that are currently in development.
Highlights
A substantial proportion of male breast cancers (MBCs) are hereditary, the molecular pathways that are activated are unknown
Since the PIK3CA/mammalian target of rapamycin (mTOR) pathway is more frequently associated with ERa positive female breast cancer (FBC), and MBC is largely characterised by ERa positive disease, we have examined the frequency of activation of the PIK3CA/mTOR pathway and its regulators in a cohort of 57 familial MBCs
PIK3CA is commonly mutated in familial male breast cancer Seven PIK3CA mutations were identified and confirmed in six samples (Table 1)
Summary
A substantial proportion of male breast cancers (MBCs) are hereditary, the molecular pathways that are activated are unknown. We examined the frequency and clinicopathological associations of the PIK3CA/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways and their regulatory genes in familial MBC. Recent studies characterising male breast cancer (MBC) show that these rare tumours are very different to their female counterparts [1,2]. Several significant targetable oncogenes are known and relatively well described in female breast cancer (FBC). Mutations of the helical or kinase domain lead to activation of the p110a kinase with subsequent downstream triggering of the mammalian target of rapamycin (mTOR) leading to cell proliferation, angiogenesis and promotion of the metastatic process [5,6]. Additional regulators of the PIK3CA/mTOR pathway include AKT1 and the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway that intersect at multiple points [7,8,9,10,11,12,13]
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