Deciphering the Role of PI3K/Akt/mTOR Pathway in Breast Cancer Biology and Pathogenesis

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

“…Activating PIK3CA point mutations are among the most common genetic aberrations in invasive breast cancer, [1][2][3][4][5][6][7][8][9][10] and several studies have shown that these mutations exist at nearly the same frequency in DCIS. [14][15][16][17] Accumulating evidence suggests that PIK3CA point mutations may also be common in other proliferative breast lesions such as benign papillomas and columnar cell lesions.…”

“…(43) Li et al 16 studied PIK3CA mutations in usual ductal hyperplasia and found no mutations in 16 lesions, in contrast to our results; the differences may be due to sample size and methodologic sensitivity, as they used less-sensitive direct Sanger sequencing. 16 The activating PIK3CA hotspot mutations seen frequently in breast cancers and proliferative lesions, most notably H1047R, E542K and, E545K, have transforming potential when overexpressed in a variety of cell culture models, [8][9][10] which arise before the most common ancestor in the genomic history of several breast carcinomas 23,44 and have thus been logically viewed as drivers of carcinogenesis. Interestingly, expression of the PIK3CA H1047R mutation at physiologic or inducible supraphysiologic levels in the mouse mammary gland leads to increased branching, duct dilation, and luminal epithelial hyperplasia.…”

“…[1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA. 3,12,13 We and other groups have previously shown that the PIK3CA genotype is concordant between ductal carcinoma in situ (DCIS) and concurrent invasive carcinoma in 66-100% of tested samples.…”

“…Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). [1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development.…”

“…[1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA.…”