ER-/PR+ breast cancer is controlled more effectively with an inflammatory inhibitor than hormonal inhibitor

Breast Cancer. 2023 May;30(3):436-452. doi: 10.1007/s12282-023-01437-6. Epub 2023 Mar 1.

Abstract

Background: The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal-positive (HR+) breast cancer patients; however, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not give the benefits of tamoxifen. Therefore ER-/PR+ breast cancer has a poor clinical outcome, and novel drug therapy for ER-/PR+ breast cancer could benefit these patients.

Methods: 53,805 gene expressions were characterized into HR+ BC and triple-negative breast cancer (TNBC) and analyzed through Breast Cancer Gene Expression Miner in 4319 breast cancer patient samples. The clinical outcomes including overall survival, distant metastasis-free survival, and relapse-free survival were obtained from the PrognoScan database containing 1190 human breast cancer patient samples. To determine the function of ERα and inflammation-related genes such as USP1, CDC20, and CASP1, we used the CRISPR-Cas9 system or gene knockdown (KD) system. To check tumor cell proliferation and migration of ERα KO breast cancer cell line, we used tamoxifen and the inflammation inhibitor Ac-YVAD-CHO. For further confirmation, cancer growth was checked with the inflammation inhibitor in ERα KO breast cancer cell line using a three-dimensional (3D) organoid tissue culture system (ex vivo).

Results: We found that gene expression in ER-/PR+ hormonal-positive breast cancer is positively related to ER-/PR- very similar to TNBC, not other HR+ breast cancer using a 4319 breast cancer patient database. Especially, inflammation-related genes, USP1, CDC20, and CASP1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of USP1, CDC20, and CASP1 inhibited tumor cell growth and metastasis in ERα KO (ER-/PR +) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to the inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo (3D organoid) models, inflammation inhibitor-specific blocks ER-/PR+ tumor proliferation and migration.

Conclusions: These findings suggest that an inflammation inhibitor might be a potential option for therapy for ER-/PR+ HR breast cancer patients.

Keywords: Ac-YVAD-CHO; CDC20; Caspase-1; ER–/PR+ hormonal breast cancer; Inflammation inhibitor; Tamoxifen; USP1.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • Inflammation / drug therapy
  • Neoplasm Recurrence, Local / drug therapy
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / genetics

Substances

  • Estrogen Receptor alpha
  • Tamoxifen
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Antineoplastic Agents, Hormonal