Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer

Table 1 Phosphatidylinositol 3-kinase pathway alterations in human breast cancers by molecular subtype

			Frequency
Gene (protein)	Alteration	Effect on signaling	Luminal (ER+)	HER2+	Basal (TN)	Reference
ErbB2 (HER2)	Amplification or overexpression	Hyperactivation of ErbB2 signaling (PI3K, MEK)	10%	~100%	0%	[30–32]
PTEN	Loss-of-function mutation or reduced expression	Hyperactivation of PI3K signaling	29-44%	22%	67%	[6, 8, 104, 105]
PIK3CA (p110α/PI3K)	Activating mutation	Hyperactivation of PI3K signaling	28-47%	23-33%	8-25%	[6, 52, 66–68, 105–107]
PIK3CB (p110β/PI3K)	Amplification	Unknown		5% of all cases		[62]
IGF1R and INSR (IGF-1R, InsR)	Receptor activation, IGF1R amplification	Activates IGF-IR/InsR signaling (PI3K, MEK)	41-48%	18-64%	42%	[108, 109]
FGFR1	Amplification, activating mutation	Hyperactivation of FGFR signaling (PI3K, MEK)	8.6-11.6%	5.4%	5.6%	[63, 110]
RPS6K1 (p70S6K)	Amplification	Unknown		3.8-12.5% of all cases		[111]
INPP4B	Reduced expression or genomic loss	Hyperactivation of PI3K signaling	10-33%	54%	53%	[64, 112]
PIK3R1 (p85α/PI3K)	Inactivating mutation	Derepression of catalytic activity of p110α		2% of all cases		[113]
AKT1	Activating mutation	Hyperactivation of AKT	2.6-3.8%	0%	0%	[65, 66, 106, 114]
AKT2	Amplification	Hyperactivation of AKT		2.8% of all cases		[115]
EGFR	Amplification	Hyperactivation of EGFR signaling (PI3K, MEK)		0.8% of all cases		[116]
PDK1	Amplification or overexpression	Hyperactivation of PDK1 (AKT, TORC1)	22%	22%	38%	[117]
KRAS	Activating mutation	Hyperactivation of PI3K and MEK		4-6% of all cases		[118, 119]

EGFR, epidermal growth factor receptor; ER, estrogen receptor; FGFR, fibroblast growth factor receptor; HER, human epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; INPP4B, inositol polyphosphate-4-phosphatase, type II; InsR, insulin receptor; MEK, mitogen-activated protein kinase kinase; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; TN, triple negative.