The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression

Abstract

Aromatase converts androgens to estrogens. Although thirdgeneration aromatase inhibitors (AIs) are important drugs in hormonal therapy for breast cancer in postmenopausal women, there are concerns about the side effects associated with the estrogen deprivation achieved with AIs. Expression of aromatase in breast cancer tissue is driven by different promoters than those in noncancer tissues; thus, suppression of aromatase expression in cancer tissues through the down-regulation of breast tumorspecific promoters would reduce the side effects associated with whole-body suppression of estrogen biosynthesis by AIs. We report that histone deacetylase inhibitor LBH589 (panobinostat) is a potent inhibitor of aromatase expression (with an IC 50 value < 25 nM). LBH589 selectively suppresses human aromatase gene promoters I.3/II, which are preferentially used in breast cancer tissue. Furthermore, using the H295R cell culture model, we found that achieving the same degree of inhibition of aromatase activity required only one-fifth as much letrozole (an AI) in the presence of 25 nM LBH589 as in the absence of LBH589. We also used an H295R/MCF7 coculture model to demonstrate the synergistic interaction of LBH589 + letrozole in suppressing the proliferation of hormone-responsive breast cancer cells. Finally, our results also indicate that LBH589 down-regulates the activity of promoters I.3/ II in an epigenetic fashion. LBH589 reduces the levels of C/EBPδ, decreases the binding of C/EBPδ, and increases the levels and binding of acetyl-histones to the promoters I.3/II. These findings provide an important basis for future clinical evaluations of LBH589 in hormone-dependent breast cancer.

Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer

“…For instance, use of SAHA as monotherapy in 14 patients with metastatic breast cancer failed to demonstrate adequate single-agent activity (49). As such, at the moment, clinical trials tend to combine HDAC inhibitors with cytotoxics, aromatase inhibitors, prodrugs and chemotherapy (41)(42)(43)(44) in order to enhance their effects against tumors.…”

“…Today many inhibitors are being studied in advanced stages of clinical trials. With regard to breast cancer research, it has been shown that HDAC inhibitors exhibit potent activity in when combined with cytotoxic drugs, aromatase inhibitors, pro-drugs and ionizing radiation (41)(42)(43)(44) (Table II).…”

The neuroprotective actions of oestradiol and oestrogen receptors

“…In addition, as local oestradiol synthesis in the brain is neuroprotective, studies should be directed to understand the mechanisms that regulate aromatase expression in the brain. The human aromatase gene promoter region is highly complex, with promoters that are used with tissue specificity 141 . Thus, aromatase tissue-specific regulation by natural or synthetic compounds opens the possibility for selective modulation of oestrogen biosynthesis within the human brain 142 .…”

Combining Emerging Agents in Advanced Breast Cancer

“…Early preclinical data suggested possible reversal of or delayed resistance to aromatase inhibition in breast cancer. For example, one study reported that panobinostat selectively suppressed human aromatase gene promoters I.3/II, which are preferentially used in breast cancer tissue [70]. Moreover, in combination with letrozole-an aromatase inhibitor-panobinostat synergistically suppressed the in vitro proliferation of hormone-responsive breast cancer cells.…”