Identification of estrogen receptor down-regulators for endocrine resistant breast cancer

Area of Science:

• Endocrinology
• Oncology
• Medicinal Chemistry

Background:

• Endocrine therapies are crucial for estrogen receptor (ER)-positive breast cancer, but resistance is a significant clinical challenge.
• Fulvestrant, an ER downregulator, faces bioavailability issues due to its hydrophobicity.
• Novel ER downregulators are needed to overcome endocrine resistance and improve treatment outcomes.

Purpose of the Study:

• To identify and characterize novel steroidal compounds with ER downregulating activity.
• To evaluate the efficacy of compounds 172 and 183 in breast cancer cell lines, including endocrine-resistant models.
• To assess the physicochemical properties, specifically hydrophobicity, of these novel compounds compared to Fulvestrant.

Main Methods:

• Steroidal compounds 172 and 183 were synthesized and tested for their ability to downregulate ER in breast cancer cell lines.
• Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess ER gene expression.
• The role of the ubiquitin-proteasomal pathway in ER downregulation was investigated using the proteasome inhibitor MG132.
• Long-term estrogen deprivation (LTED) MCF-7 cells were used to model endocrine resistance.
• Hydrophobicity and solubility of compounds 172 and 183 were determined.

Main Results:

• Compounds 172 and 183 significantly downregulated ER in multiple breast cancer cell lines without affecting ER gene expression.
• ER downregulation by these compounds was mediated through the ubiquitin-proteasomal pathway, as evidenced by MG132 treatment.
• Compounds 172 and 183 demonstrated efficacy in downregulating ER in LTED MCF-7 cells, an endocrine-resistant model.
• These novel compounds exhibited improved solubility and reduced hydrophobicity compared to Fulvestrant.

Conclusions:

• Compounds 172 and 183 represent a novel class of steroidal ER downregulators.
• Their mechanism involves the ubiquitin-proteasomal degradation of ER.
• These compounds show potential for treating endocrine-resistant breast cancer due to their efficacy and improved physicochemical properties.
• Compounds 172 and 183 warrant further investigation as lead compounds for developing new breast cancer therapies.