Breast cancer (BC) is the most common cancer in women, with an estimated 276,500 new cases and 42,000 deaths in the US in 2020. BCs can be further classified into three subtypes, based on their molecular identifications: Estrogen Receptor alpha (ERα)-positive, Her2 (human epidermal growth factor receptor 2)-positive, and triple (ERα-, PR (progesterone receptor)-, and Her2)-negative breast cancer (TNBC). ERα-positive BC accounts for the largest subtype, with approximately 70% of BC patients.
Our lab studies how transcription and the signaling networks control cell fate in BCs. Ultimately, we hope to harness the knowledge gained from these studies to help fight against BCs. Currently, we are working toward answering the following questions:
- How does the PML spliced isoform, PML1, elicits its pro-tumorigenic activity to promote cell proliferation, migration, and invasion?
- How can one target endocrine-resistant ERα-positive BC?
The mechanism underlying PML1-mediated oncogenic activity in BCs
The promyelocytic leukemia protein (PML) is a well-established tumor suppressor known to play a role in cell proliferation, apoptosis, DNA damage repairs, and transcription. However, recent studies suggest that PML acts as an oncogene in BC and glioblastoma (GBM). Specifically, we show that a loss of PML by knockdown inhibits the proliferation of the ERα-positive BC cells. Conversely, ectopic expression of PML1, the most abundant PML spliced isoform in BC, augments the growth, migration, and invasion of ERα-positive BC cells. In contrast, the expression of PML4, a well-studied PML isoform with tumor suppression activity, does the opposite. We are the first to demonstrate that the spliced isoform PML1 functions as an oncoprotein. Accordingly, clinical data show that high expression of PML1 mRNA in ERα-positive BC correlates with a poor prognosis.
Targeting endocrine-resistant, ERα-positive BC
More than 70% of all BCs are ERα-positive. While initial treatments of current ERα-targeted endocrine therapies are successful, patients with metastasis eventually develop resistance. Among these patients, acquired ERα mutations have been established as a new mechanism of drug resistance for ERα-positive BC patients. ERα is a hormone-activated transcription factor that controls the expression of a network of genes that encode proteins necessary to drive cell cycle progression. Molecular and biochemical studies indicated that these ERα mutants are constitutively active to promote cell/tumor growth.
With Dr. Sichun Yang in the Nutrition department, we have recently identified a novel interface between the DNA- and ligand-binding domains. Mutations at the interface disrupt estrogen (E2)-induced ERα-mediated transcription activity. This observation indicated that the integrity of the interface is critical for ERα transcription activity and raises the possibility that small chemical molecules that bind to the domain interface may regulate ERα activity. With this goal in mind, we screened and identified several FDA-approved drugs, including a drug termed T4, with the ability to bind ERα domain interface and to inhibit E2-induced ERα activity. We are currently characterizing T4 for its ability to inactivate endocrine-resistant mutant ERα activity.
- Pai CP, Wang H, Agarwal N, Adams J, Liu Z, Seachrist D, Keri R, Schiemann W, Kao HY.
"The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer." Research Square [Preprint]. September 8th, 2023
- Du Z*, Wang H*, Wu C, Buck M, Zheng W, Hansen AL, Kao HY, Yang S
"Phosphorylation modulates estrogen receptor disorder by altering long-range hydrophobic interactions." BioRxiv548966 [Preprint]. July 15, 2023 [cited 2023 July 18].
- Fang, W. Y., Kuo Y. Z,, Chang J. Y., Hsiao J. R., Kao H. Y., Tsai, S. T., and Wu L. W.
"The tumor suppressor TGFBR3 blocks lymph node metastasis in head and neck cancer."
- Alhazmi N., Pai CP., Albaqami A., Wang H., Zhao X., Chen M., Hu P., Guo S., Starost K., Hajihassani O., Miyagi M., and Kao HY
“The promyelocytic leukemia protein isoform PML1 is an oncoprotein and a direct target of the antioxidant sulforaphane (SFN).”
Biophys Acta Mol Cell Res. 1867, 118707 (2020).
- Huang W., Peng Y., Kiselar J., Zhao X., Albaqami A., Mendez D., Chen Y., Chakravarthy S., Gupta S., Ralston C., Kao H.Y., Chance M.R., Yang S.
“Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains.”
Nat Commun. 30;9(1):3520(2018).
- Zhang Y. Y., Tabataba H., Liu X. Y., Wang J. Y., Yan X. G., Farrelly M., Jiang C. C., Guo S. T., Liu T., Kao H. Y., Thorne R. F., Zhang X. D., and Jin L.
“ACTN4 regulates the stability of RIPK1 in melanoma”
Oncogene 37 (29): 4033-45 (2018).
- Pan S. C., Li C. Y., Kuo C. Y., Kuo Y. Z., Fang W. Y., Huang Y. H., Hsieh T. C., Kao H. Y., Kuo Y., Kang Y. R., Tsai W. C., Tsai S. T., and Wu L. W.
“The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing”
Sci Rep 8 (1): 5458 (2018).
- Hsu K. S. and Kao H. Y.
“PML: Regulation and multifaceted function beyond tumor suppression”
Cell Biosci 8: 5 (2018).
- Zhao X., Khurana S., Charkraborty S., Tian Y., Sedor J. R., Bruggman L. A., and Kao H. Y.
“alpha Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes”
J Biol Chem 292 (5): 1637-47 (2017).
- Hsu K. S., Zhao X., Cheng X., Guan D., Mahabeleshwar G. H., Liu Y., Borden E., Jain M. K., and Kao H. Y.
“Dual regulation of Stat1 and Stat3 by the tumor suppressor protein PML contributes to interferon alpha-mediated inhibition of angiogenesis”
J Biol Chem 292 (24): 10048-60 (2017).
- Hsu K. S., Guan B. J., Cheng X., Guan D., Lam M., Hatzoglou M., and Kao H. Y.
“Translational control of PML contributes to TNFalpha-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs”
Cell Death Differ 23 (3): 469-83 (2016).
- Zhao X., Hsu K. S., Lim J. H., Bruggeman L. A., and Kao H. Y.
“alpha-Actinin 4 potentiates nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-kappaB) activity in podocytes independent of its cytoplasmic actin binding function”
J Biol Chem 290 (1): 338-49 (2015).
- Lim L. M., Zhao X., Chao M. C., Chang J. M., Chang W. C., Kao H. Y., Hwang D. Y., and Chen H. C.
“Novel Vitamin D Receptor Mutations in Hereditary Vitamin D Resistant Rickets in Chinese”
PLoS One 10 (9): e0138152 (2015).
- Kao H. Y.
“The actinin family proteins: biological function and clinical implications”
Cell Biosci 5: 48 (2015).
- Guan D. and Kao H. Y.
“The function, regulation and therapeutic implications of the tumor suppressor protein, PML”
Cell Biosci 5: 60 (2015).
- Guan D., Lim J. H., Peng L., Liu Y., Lam M., Seto E., and Kao H. Y.
“Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death”
Cell Death Dis 5: e1340 (2014).
- Guo S., Cheng X., Lim J. H., Liu Y., and Kao H. Y.
“Control of antioxidative response by the tumor suppressor protein PML through regulating Nrf2 activity”
Mol Biol Cell 25 (16): 2485-98 (2014).