AROMATASE INTERACTING PARTNER IN BREAST (AIPB), LOCALIZED TO THE MITOCHONDRIA ASSOCIATED-ER MEMBRANE (MAM) SYNTHESIZES ESTRADIOL IN TRIPLE-NEGATIVE BREAST CANCER (ER-/PR-/ HER2- OR TNBC)
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Author
Tinker, Hunter BaleyKeyword
BiochemistryCellular biology
Medicine
Aromatase, Aromatase Interacting Partner in Breast (AIPB), Breast Cancer, Estradiol, Mitochondria Associated-ER Membrane (MAM), Tumorigenesis
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AROMATASE INTERACTING PARTNER IN BREAST (AIPB), LOCALIZED TO THE MITOCHONDRIA ASSOCIATED-ER MEMBRANE (MAM) SYNTHESIZES ESTRADIOL IN TRIPLE-NEGATIVE BREAST CANCER (ER-/PR-/ HER2- OR TNBC)Abstract
Estradiol (E2), synthesized by Endoplasmic Reticulum (ER) resident enzyme, aromatase, is essential for the development of sex characteristics and fertility in females. Produced in the ovaries and adipose tissue, Estradiol levels often become unregulated, supporting breast tumorigenesis. Therapeutics aim to reduce these levels via the inhibition of Aromatase or the modulation of the estrogen receptor (Er+). Aromatase Inhibitors and Estradiol agonists are effective for treating most breast cancers, but treatment challenges present for Triple-negative breast cancer (Er-/Pr-/Her2-). Receptors for Triple-negative breast cancer (Er-/Pr-/Her2-), and the rate-limiting enzyme, Aromatase, are absent. From human breast tissue, we cloned a 207 amino acid cDNA encoding for a 21.7-kDa protein, entitled Aromatase Interacting Partner in Breast (AIPB), that directly interacts with Aromatase. AIPB is present in affected and unaffected breast tissue. A stable selection was developed (Puromycin) for MDA-MB-231 (Er-/Pr-/Her2-), after AIPB was subcloned into a vector with a TET-ON promoter. Overexpression of AIPB in Er+/Pr+/Her2- and Er-/Pr-/Her2+ resulted in the decreased levels of Estradiol (E2). In the tumor microenvironment, serine proteases are overexpressed, aiding in cancer metastasis and invasion. I hypothesized that serine proteases may be proteolyzing AIPB, resulting in elevated Estradiol levels, in MDA-MB-231 (Er-/Pr-/Her2-) cells. A time course study (12-96h) was performed, with serine protease inhibitor, Epigallocatechin gallate (EG), in the presence and absence of Doxycycline (250 μg/mL). Data suggests that AIPB expression is stabilized between the concentrations of 5-50 μM in the presence of Epigallocatechin gallate (EG) and plays a central role in Estradiol (E2) synthesis (Er-/Pr-/Her2-), either directly or indirectly. In conclusion, AIPB may permit early detection of Triple-negative breast tumors, acting as a biomarker at the Mitochondria Associated-ER Membrane (MAM).Description
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