Abstract
Abstract Background: We have recently shown that the luminal B subtype breast cancer (BC) is associated with PI3K molecular signature. Breast tumors of the luminal B subtype generally have lower ER expression levels and/or activity and are more aggressive and less sensitive to endocrine therapy when compared to the luminal A tumors. To further investigate the role of PI3K signaling in BC luminal types and endocrine resistance, we have characterized an array of luminal A and B cell lines, as well as their endocrine resistant derivatives, to examine how modulation of the PI3K pathway can influence ER activity and endocrine sensitivity. Materials and Methods: We focused on endocrine resistant derivatives of two luminal A (ZR75-1 and BT483) and two luminal B (ZR75-B and CAMA-1) cell lines. Resistant clones were developed by long-term (>6 months) endocrine treatment [estrogen deprivation (ED) or ED plus Tamoxifen (Tam)]. IC50 values of the PI3K inhibitor BEZ-235 were determined in the parental and the endocrine resistant lines, and qRT-PCR was performed to measure the effect of the inhibitor on mRNA levels of ER and its regulated genes (e.g. PR, CAV1, IGF1R and IRS1). Cells were also treated (4 days) with Tam, BEZ-235, or the combination and growth inhibition assays were conducted to assess the drugs efficacy. Inducible PTEN knockdown clones were established in MCF7L and BT483 cell lines. Endocrine sensitivity of these clones was studied in vitro and in vivo, using xenograft mouse models. Results: Ten days of treatment showed that all parental lines were sensitive to endocrine therapy. In contrast, stabilized endocrine resistant cell lines showed similar cell growth rate under Tam or ED treatment compared to control E2 treatment (p>0.05). ZR75-1 endocrine resistant derivatives acquired higher sensitivity to BEZ-235 treatment compared to the parental (p<0.05); a finding that is currently being confirmed in other cell line models. BEZ-235 increased expression of ER and its targeted genes in all 4 parental cell lines (p<0.05). BEZ-235 and Tam administered together additively suppressed cell growth in all 4 parental cell lines (p<1E-5). PTEN knockdown significantly increased the levels of pAkt and decreased the expression of ER and its regulated genes (PR and IGF1R). In vivo xenograft mouse models showed that PTEN knockdown renders tumors continued growth under ED, in contrast to the regression of parental/control tumors under this endocrine regimen (p<0.05). Discussion: The inverse association between PI3K and ER pathways in luminal BC cell lines validates the relevance of these models for further studies. Endocrine resistant phenotype may be partially caused by activated PI3K signaling. Our data suggest that inhibition of PI3K signaling can restore ER levels and/or activity, thereby reversing the aggressive and hormonal-refractory phenotype of the tumors, and achieving improved endocrine therapy response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2290. doi:10.1158/1538-7445.AM2011-2290
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