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MiR-152/PKM2/SLC7A5 axis in breast cancer development, chemo- and radiation-treatment response

Award Number: R01CA263506
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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MiR-152/PKM2/SLC7A5 axis in breast cancer development, chemo- and radiation-treatment response - Breast cancer (BCa) is the leading cause of women cancer mortality worldwide, and triple negative breast cancer (TNBC) cells accounts for 15-20% BCa. However, higher therapeutic resistance and lower survival of TNBC patients remain the major hinder of BCa treatment. Doxorubicin (Dox) and radiation are commonly used for TNBC treatment. In our preliminary study, we found that TNBC showed much lower expression levels of miR-152. Higher expression levels of zeste homologue 2 (EZH2) and DNA hypermethylation were involved in miR-152 suppression in TNBC cells. To understand mechanism of miR-152 suppression, and role and mechanism of miR-152 in regulating cancer development and Dox- and radiation-induced resistance, we performed a lot of preliminary experiments to identify what molecules that were potential miR-152 direct targets as well as that were upregulated in Dox-resistant TNBC or PDX tumor tissues. We found that pyruvate kinase muscle 2 (PKM2), solute Carrier Family 7 Member 5 (SLC7A5), and polypyrimidine tract-binding protein (PTBP1) as direct targets of miR-152 with potential ability to converse Dox-mediated resistance. PKM2, SLC7A5 and PTBP1 levels were increased when miR-152 expression was suppressed in TNBC cells and PDX model. We found that miR-152 suppression played an important role in mediating TNBC metabolic reprogramming, Warburg effect switch, tumor growth and Dox resistance through PKM2/SLC7A5/PTBP1. We showed that overexpression of miR-152 or PKM2 knockdown rendered TNBC cells more sensitive to radiation treatment. These new findings create new opportunity to investigate mechanism of TNBC therapeutic resistance. We hypothesize that resistance to chemotherapy and radiation treatment, metabolic reprogramming, and TNBC development are induced by miR-152 suppression and upregulation of PKM2, SLC7A5, and PTBP1. To test this central hypothesis, we will perform experiments through three aims. In Aim 1, we will investigate role and mechanism of miR-152 suppression in TNBC cells in doxorubicin- and radiation-induced resistance; and role and mechanism of PKM2 switch and induction via alternative splicing by miR-152 suppression to induce Warburg effect, therapeutic resistance, and tumor growth. In Aim 2, we will determine role and mechanism of miR- 152/SLC7A5/PTBP1 pathway in regulating metabolic reprogramming and Warburg effect switch, and in mediating doxorubicin- and radiation-induced therapeutic resistance. In Aim 3, we will determine whether miR-152 suppression and PKM2 induction regulate tumor angiogenesis through CXCL8 expression using a humanized chimeric tumor model; and whether levels of miR-152, PKM2, HIF-1α, hnRNPA3, SLC7A5, and PTBP1 are correlated each other, and are correlated with therapeutic responses and with the cancer stages and survival. This R01 project will identify mechanisms of therapeutic resistance, and metabolic reprogramming; and provide information for developing new treatment option of TNBC in the future.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $644,810 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	5	3/30/2026	NON-COMPETING CONTINUATION	$644,810
														Subtotal = $644,810

Issue Date FY: 2025 ( Subtotal = $644,810 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$64,481
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	4	3/27/2025	NON-COMPETING CONTINUATION	$580,329
														Subtotal = $644,810

Issue Date FY: 2024 ( Subtotal = $264,296 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	3	3/26/2024	NON-COMPETING CONTINUATION	$232,055
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$32,241
														Subtotal = $264,296

Issue Date FY: 2023 ( Subtotal = $631,914 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	2	4/4/2023	NON-COMPETING CONTINUATION	$631,914
														Subtotal = $631,914

Issue Date FY: 2022 ( Subtotal = $644,810 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	1	8/9/2022	NEW	$0
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	1	3/16/2022	NEW	$644,810
														Subtotal = $644,810

Grand Total All Awards = $2,830,640

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MiR-152/PKM2/SLC7A5 axis in breast cancer development, chemo- and radiation-treatment response

Award Number: R01CA263506

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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