Akt kinases in breast cancer and the results of adjuvant therapy

Abstract

The regulation of cell proliferation and cell survival in breast cancer is a complex interplay between steroid hormones, growth factors and their receptors. The understanding of the signalling pathways involved in these processes may help us find predictive factors for tumour aggressiveness and therapy resistance. Already recognised is the importance of the oestrogen receptor (ER) status of the tumour for predicting the benefit from endocrine treatment [1].Although it has not yet been fully established from clinical materials, experimental studies suggest that overexpression of different growth factor receptors in breast cancer makes cells less sensitive to tamoxifen and other cytotoxic drugs. These receptors include insulin-like growth factor CI = confidence interval; CMF = cyclophosphamide-methotrexate-5-fluorouracil; ER = oestrogen receptor; FITC = fluorescein isothiocyanate; pAkt = phosphorylated Akt; PI3-K = phosphatidylinositol 3-kinase; RR = rate ratio. Stål et al., licensee BioMed Central Ltd (Print ISSN 1465-5411; Online ISSN 1465-542X). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any non-commercial purpose, provided this notice is preserved along with the article's original URL. AbstractBackground: The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50]. In the present study, we showed PTPN2 gene loss as a new potential marker of endocrine resistance.…”

“…S-phase fraction (SPF) was previously determined by flow cytometry [18], and mutations in PIK3CA exon 9 or 20 were assessed by single-strand conformational polymorphism (SSCP) and sequencing [19]. Levels of AKT phosphorylated at S473 (pAKT) were estimated by immunohistochemistry [20]. Breast cancer subtypes were defined according to St Gallen 2011 [21] as follows: Luminal A (ER+, HER2-, SPF<12%), Luminal B1 (ER+, HER2-, SPF≥12%), Luminal B2 (ER+, HER2+), HER2-like (ER-, HER2+), and Triple-negative (ER-, HER2-), where HER2 status was defined by its gene copy number.…”

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

“…The data material was previously described (14). In this study we have used data from a subset of the postmenopausal patients consisting of 272 patients with median age 59 years (range: 45 -71) for whom data on Akt1, Akt2 and pAkt was available from a previous study (10). The period of follow-up has now been extended.…”

“…The expression of Akt1, Akt2 and pAkt was analyzed by immunohistochemistry as previously reported (10). Goat polyclonal antibodies against Akt1 and Akt2 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), and a sheep polyclonal antibody against the phosphorylated serine residue in position 473 of human Akt1 (Upstata Biotechnology, Lake Placid, NY, USA) were used for immunostaining.…”

“…Although pAkt expression is more closely related to Akt1 than to Akt2 in breast cancer (8,10,11), it has been reported that Akt2 is also frequently upregulated in HER2-positive breast tumors and may contribute to tumor aggressiveness (12). However, recent studies have shown that overexpressed Akt2 is a favorable prognostic factor (11,13).…”