Abstract
Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 114-126 |
| Number of pages | 13 |
| Journal | Hormones and Cancer |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1 2016 |
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ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Oncology
- Endocrinology
- Endocrine and Autonomic Systems
- Cancer Research
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Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer. / Agyeman, Abena S.; Jun, Wesley J.; Proia, David A.; Kim, Caroline R.; Skor, Maxwell N.; Kocherginsky, Masha; Conzen, Suzanne D.
In: Hormones and Cancer, Vol. 7, No. 2, 01.04.2016, p. 114-126.Research output: Contribution to journal › Article
TY - JOUR
T1 - Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer
AU - Agyeman, Abena S.
AU - Jun, Wesley J.
AU - Proia, David A.
AU - Kim, Caroline R.
AU - Skor, Maxwell N.
AU - Kocherginsky, Masha
AU - Conzen, Suzanne D.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.
AB - Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.
UR - http://www.scopus.com/inward/record.url?scp=84957701921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957701921&partnerID=8YFLogxK
U2 - 10.1007/s12672-016-0251-8
DO - 10.1007/s12672-016-0251-8
M3 - Article
VL - 7
SP - 114
EP - 126
JO - Hormones and Cancer
JF - Hormones and Cancer
SN - 1868-8497
IS - 2
ER -