Divergent Activity of the Pseudogene PTENP1 in ER-Positive and Negative Breast Cancer.

Transcripts derived from the PTEN pseudogene (PTENP1) function as decoys to adsorb miRNAs targeting the PTEN tumor suppressor for degradation, and PTENP1 upregulation is known to inhibit growth in preclinical cancer models. Here, PTENP1 3'UTR transduction influences PTEN, AKT/mTOR signaling, and tumor progression in estrogen receptor (ER)-positive and -negative breast cancer cells. PTENP1 upregulation decreases PTEN gene expression in the ER-positive MCF7 and T47D human breast carcinoma cells and accelerates MCF7 tumor growth in vivo Of note, PTENP1 transduction significantly decreases ERα (ESR1) mRNA and protein levels in MCF7 xenografts with a concomitant increase in hsa-miR-26a, a miRNA known to target ESR1 In the ER-negative MDA-MB-231 and C3HBA breast cancer cells, upregulation of PTENP1 increases PTEN gene expression with no influence on hsa-miR-26a, ESR1, or ERα expression. While PTENP1 transduction did not influence the growth rate of human MDA-MB-231 xenografts, PTENP1 upregulation profoundly reduces its metastatic propensity. Furthermore, PTENP1 significantly inhibits the growth rate of ER-negative C3HBA murine breast cancer xenografts. PTENP1 transduction had no influence on doxorubicin cytotoxicity in ER-positive MCF7 cells but an increase in doxorubicin sensitivity was observed in the ER-negative MDA-MB-231 cells. In summary, while PTENP1 upregulation decreased PTEN transcript levels and stimulated the growth of ER-positive breast cancers, increased PTEN transcript levels and inhibited tumor progression was observed in the ER-negative cells.Implications: This report highlights the profound biological activity of PTENP1 in breast cancer, which is dictated by the hormone receptor status. Mol Cancer Res; 16(1); 78-89. ©2017 AACR.

Activation of Akt characterizes estrogen receptor positive human breast cancers which respond to anthracyclines.

Anthracyclines are key components of human breast cancer chemotherapy. Here, we explored the role of Akt signaling in anthracycline resistance.The antitumor activity of doxorubicin and Akt inhibitor A-443654 alone or combined was examined in estrogen receptor (ER) positive and negative human breast cancer cell lines. Further, we examined mRNA changes induced by anthracyclines in locally advanced breast cancers biopsied before and after treatment in two clinical trials.Doxorubicin increased Akt phosphorylation in ER positive MCF7 and T47D cell lines, with no effect in ER negative MDA-MB231 breast cancer cells. A-443654 was significantly more cytotoxic in doxorubicin-resistant compared to doxorubicin-naïve MCF7. This difference was not observed in MDA-MB231. Among 24 patients, AKT1 gene expression increased 24 hrs after the initial epirubicin exposure in ER positive tumors responding to therapy (n=6), as compared to ER positive non-responders (n=7) or ER negative tumors (n=11). In contrast, AKT1 mRNA changes after 16 weeks of doxorubicin were unrelated to clinical response and ER status (n=30).In conclusion, rapid Akt activation was observed in ER positive breast cancers which responded to anthracyclines. Increased cytotoxicity of A-443654 in doxorubicin-resistant MCF7 cells indicates a possible role for Akt inhibitors in ER positive breast cancers where chemoresistance evolves.

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function.

PURPOSE: PTEN is an important tumor suppressor in breast cancer. Here, we examined the prognostic and predictive value of PTEN and PTEN pseudogene (PTENP1) gene expression in patients with locally advanced breast cancer given neoadjuvant chemotherapy. METHODS: The association between pretreatment PTEN and PTENP1 gene expression, response to neoadjuvant chemotherapy, and recurrence-free and disease-specific survival was assessed in 364 patients with locally advanced breast cancer given doxorubicin, 5-fluorouracil/mitomycin, or epirubicin versus paclitaxel in three phase II prospective studies. Further, protein expression of PTEN or phosphorylated Akt, S6 kinase, and 4EBP1 was assessed in a subgroup of 187 tumors. RESULTS: Neither PTEN nor PTENP1 gene expression level predicted response to any of the chemotherapy regimens tested (n = 317). Among patients without distant metastases (n = 282), a high pretreatment PTEN mRNA level was associated with inferior relapse-free (RFS; p = 0.001) and disease-specific survival (DSS; p = 0.003). Notably, this association was limited to patients harboring TP53 wild-type tumors (RFS; p = 0.003, DSS; p = 0.009). PTEN mRNA correlated significantly with PTENP1 mRNA levels (r s = 0.456, p < 0.0001) and PTEN protein staining (r s = 0.163, p = 0.036). However, no correlation between PTEN, phosphorylated Akt, S6 kinase or 4EBP1 protein staining, and survival was recorded. Similarly, no correlation between PTENP1 gene expression and survival outcome was observed. CONCLUSION: High intratumoral PTEN gene expression was associated with poor prognosis in patients with locally advanced breast cancers harboring wild-type TP53.

The emergence of targeted drugs in breast cancer to prevent resistance to endocrine treatment and chemotherapy.

INTRODUCTION: Deregulated signaling pathways are associated with resistance to chemotherapy and endocrine treatment, providing a rationale for the implementation of novel targeted therapies in breast cancer therapy. Key molecules targeted therapeutically in ongoing clinical breast cancer trials are phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR), Src, insulin-like growth factor 1 receptor, heat shock protein-90, histone deacetylases, cyclin-dependent kinases (CDKs), Notch and human epidermal growth factor receptors (HERs). AREAS COVERED: This review provides an overview of novel targeted agents currently explored in clinical breast cancer trials and registered in ClinicalTrials.gov. The main focus will be on their ability to prevent or reverse endocrine resistance and chemoresistance in breast cancer. EXPERT OPINION: HER2 targeted agents have extended survival substantially, both in the adjuvant and metastatic setting, pointing to a crucial dependency on this pathway in HER2-amplified breast cancer, including drug resistance reversal. While data on mTOR inhibitors are encouraging and preliminary results on CDK4/6 and Src inhibitors exciting, so far other targeted agents have been of limited benefit when added in concert with conventional therapies. Future clinical trials should systematically explore biomarkers and defects in functional gene cascades to identify relevant biological mechanisms to be targeted therapeutically in breast cancer.