SUN-273 - Regulation of Estradiol Synthesis in Triple-Negative Breast Cancer Cells by AIPB

Breast cancer is a devastating health problem among women at any stage of life, which can occur as early as the start of childbearing age. Death rates of breast cancer have decreased due to better management of screening efforts; however, breast cancer is still the leading cause of cancer-related deaths in women in the United States. Breast cancer is usually hormonally regulated, where Estrogen (Er⁺), Progesterone (Pr⁺), and Human Epidermal Growth Factor Receptor (Her2⁻) expression is associated with an increase in tumorigenesis. The exact mechanism of development or change in expression of these receptors is unknown. Triple-negative breast cancer (TNBC) minimally expresses these receptors (ER⁻/ Pr⁻/Her2⁻) or is absent, which raises challenges in the treatment of these patients. We identified a new 22-kDa protein from human breast tissue, Aromatase Interacting Partner in Breast (AIPB), which is also expressed in affected tumorigenic breast tissues. Direct visualization and biochemical experiments showed that AIPB is mainly localized at the mitochondria associated at the ER membrane (MAM). We placed AIPB in a vector under the control of Tet promoter and developed a stable MDA-MB-231-AIPB cells for a uniform expression with tetracycline. In a cellular model, we have observed that stress, following a heat shock, significantly increased AIPB expression with a reduction in estradiol synthesis, suggesting that AIPB expression is proportional to estradiol synthesis. Therefore, we hypothesized that AIPB expression might play a critical role in TNBC independent of cAMP. We observed that estrogen stimulator, a-Zeranol, induced AIPB expression having a maximum at 24 hours and then gradually decreased at 96 hours, like the level of unstimulated cells, suggesting that AIPB might play a regulatory role in estradiol synthesis. Antihelminth drug Pyrvinium pamoate (PvR) is used to reduce various cancers, including TNBC. We incubated TNBC MDA-MB-231-AIPB cells with a 50,000-fold difference in concentrations of PvR (1.0 ng to 50,000 ng) in the presence and absence of tetracycline and determined AIPB expression by immunoblotting and activity by radioimmunoassay (RIA). The cells were induced with increased concentration of PvR and Doxycycline, together resulted reduction in estradiol with an increase in AIPB expression with more than 20.0 mg. Protein finger printing followed by immunoblotting showed that PvR associates with AIPB in a complex from 12-18 ug of PvR, suggesting PvR remains associated with AIPB in the MAM. Therefore, we conclude that the estradiol synthesis is dependent on AIPB expression and is likely critical for estradiol synthesis in TNBC cells.

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