Dysregulated PTEN‐PKB and negative receptor status in human breast cancer

Abstract

Recent studies demonstrate that abnormalities in PTEN may be one of the most frequent genetic events observed in human cancers. PTEN dysfunction leads to tumorigenesis through unopposed survival signals mediated via activated protein kinase B (PKB), which may also be associated with hormone-independence. We therefore investigated the relationship between PTEN-PKB and receptor status in human breast cancer. Several molecular variables, including immunohistochemical staining for PTEN, PKB (phosphorylated on ser473), p53 and p21 were evaluated. The p53 gene was sequenced from exons 2-11. Seventy-eight participants in a randomised breast cancer trial served as the cohort for our study. Twenty-eight of 77 (36%) patients' tumours demonstrated absent or reduced PTEN expression; 17 of 78 (22%) tumours over-expressed P-PKB. A significant inverse relationship was observed between reduced PTEN and increased P-PKB expression. Reduced PTEN also correlated with reduced ER or PR expression. None of the molecular variables correlated with survival. ER and PR negative tumours, however, experienced a significantly inferior disease-free survival than other ER/PR status tumours. Immunohistochemical analyses of ER expression in mammary carcinomas arising in PTEN heterozygous knockout mice did not demonstrate a reduction in ER immunoreactivity, in comparison to wildtype mice. Our data demonstrate that the PTEN-PKB pathway is abnormal in approximately 1 ⁄3 of lymph node negative breast cancer. Dysregulated PTEN-PKB was also associated with reduced ER/PR expression, but this does not appear to be a simple direct causal relationship. These observations support the contention that dysregulation in PTEN-PKB contributes to disease progression and hormone resistance of human breast cancer.

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…Furthermore, ER and PR were still expressed in four of the five tumors that had lost the wild-type Pten allele (Figure 3a and b). These results suggest that loss of Pten does not prevent ER expression in mammary cancers, consistent with another study examining ER expression in mammary lesions in Pten þ /À mice that do not carry a transgene (Shi et al, 2003). Neu (HER2, ErbB2) is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases (Olayioye et al, 2000).…”

“…Loss of Pten is usually associated with ER À human breast cancers (Garcia et al, 1999;Perren et al, 1999;Shi et al, 2003). We have previously reported that inactivation of one allele of Pten accelerates mammary tumorigenesis in MMTV-Wnt-1 TG mice, and 70% of the resulting tumors have lost the wild-type allele of Pten (Li et al, 2001).…”

Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer

“…PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibits PKB activation by virtue of its dephosphorylating role in reverting PIP 3 to PIP 2 . We and others have documented that PTEN is underexpressed in approximately 30% of human breast cancers, 27,28 resulting in upregulation of PKB activity, which in turn is associated with reduced patient survival. 29 Hyperthermia has been demonstrated in Phase III randomized trials to benefit patients with both improved local control 1,4,5 and survival.…”

“…One possible explanation might be related to the endogenous PTEN-PKB pathway whereby we have previously documented that the more sensitive MDA-MB-468 cells lack PTEN and have increased P-PKB expression. 27 In contrast, the MCF-7 cells have preserved PTEN expression, and undetectable phospho-PKB (in the unstimulated state). Hence, potentially, the MDA-MB-468 cells may be dependent upon activated PKB for their continued proliferation and survival.…”

“…In addition, the PTEN-PKB pathway is relevant in human breast cancer in that dysregulation of this pathway, as indicated by immunohistochemistry studies of patients' surgical samples, was associated with negative ER/PR status. 27 Hence, a logical extension of our research was to evaluate the potential efficacy of combining HT with a method to neutralize the PKB survival pathway.…”