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The Role of FOXCI in Basal-like Breast Cancer

Award Number: R01CA151610
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/14/2011
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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The Role of FOXCI in Basal-like Breast Cancer - Abstract Basal-like breast cancer (BLBC) consistently expresses genes typical of normal basal/myoepithelial cells of the breast and comprises up to 25% of all breast cancer. It is associated with aggressive clinical behavior and a high rate of metastasis to the lung. The organ-preferential metastasis of BLBC is poorly understood. Of note, the vast majority of breast tumors arising in BRCA1 mutation carriers display a basal-like phenotype. Little is currently known about the molecular basis of the tissue and subtype-specific features of BRCA1-mutant breast cancer. We found that the transcription factor FOXC1 is exclusively induced in BLBC including BRCA1-mutant breast cancer and correlates with poor clinical outcome. It regulates breast cancer cell function by inducing NF- κB and other cancer-associated signaling pathways. Its overexpression in the mouse mammary gland increases the luminal progenitor population, which is postulated to be the cell of origin of BRCA1-mutant breast cancer. We also found that FOXC1 and its targets CXCL1, 2, and 8 chemokines are essential for BLBC lung metastasis. These chemokines act in concert with lung fibroblasts to induce endothelial cell migration in vitro. We therefore hypothesize that FOXC1 counteracts the detrimental effects of BRCA1 mutations in breast cells and plays a critical role in basal-like BRCA1-mutant breast cancer development. In addition, we hypothesize that the chemokines CXCL1, 2, and 8 mediate the effect of FOXC1 on BLBC lung metastasis by engaging lung fibroblasts to induce angiogenesis. In Aim 1, we will determine the role of FOXC1 in the development of BRCA1-mutant breast cancer with the basal-like phenotype. BRCA1-mutant breast cancer cell models will be used to test whether FOXC1 signaling pathways regulate cell function and counteracts the increase of reactive oxygen species in breast epithelial cells with BRCA1 mutations or deficiency. We will determine whether FOXC1 regulates mammary tumorigenesis in BRCA1-mutant xenograft models and a mammary-specific BRCA1-deficient mouse model. In Aim 2, we will define a FOXC1/chemokine-mediated mechanism for BLBC lung metastasis. Tail vein injection mouse models will be used to investigate whether the FOXC1-induced chemokines promote the proliferation and survival of metastatic breast cancer cells in the lung tissue microenvironment. We will determine whether FOXC1 overexpression in BLBC leads to increased angiogenesis in lung metastases mediated by chemokine-directed crosstalk between metastatic breast cancer cells and lung fibroblasts. We will further investigate the mechanism whereby FOXC1 regulates the three chemokines in BLBC cells. Basal-like BRCA1-mutant breast cancer development and BLBC metastasis are poorly understood areas that are of paramount importance in breast cancer. Our results will shed light on their biological basis and will lay down a foundation for new approaches that can prevent and treat FOXC1- overexpressing breast cancer.


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: 2025 ( Subtotal = -$1 )
2025	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	10	6/13/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	10	3/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $407,313 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	001	10	5/24/2022	NON-COMPETING CONTINUATION	$33,251
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	10	12/23/2021	NON-COMPETING CONTINUATION	$374,062
														Subtotal = $407,313

Issue Date FY: 2021 ( Subtotal = $415,625 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	9	1/22/2021	NON-COMPETING CONTINUATION	$415,625
														Subtotal = $415,625

Issue Date FY: 2020 ( Subtotal = $415,625 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	8	1/8/2020	NON-COMPETING CONTINUATION	$415,625
														Subtotal = $415,625

Issue Date FY: 2019 ( Subtotal = $403,156 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	7	1/11/2019	NON-COMPETING CONTINUATION	$403,156
														Subtotal = $403,156

Issue Date FY: 2018 ( Subtotal = $415,527 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	6	1/25/2018	COMPETING CONTINUATION	$415,527
														Subtotal = $415,527

Issue Date FY: 2017 ( Subtotal = -$98 )
2017	2015	JOHN WAYNE CANCER INSTITUTE	2200 SANTA MONICA BLVD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	3/29/2017	NON-COMPETING CONTINUATION	-$98
														Subtotal = -$98

Issue Date FY: 2015 ( Subtotal = $346,525 )
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	1/26/2015	NON-COMPETING CONTINUATION	$346,525
														Subtotal = $346,525

Issue Date FY: 2014 ( Subtotal = $336,129 )
2014	2014	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	3/26/2014	NON-COMPETING CONTINUATION	$336,129
														Subtotal = $336,129

Issue Date FY: 2013 ( Subtotal = $325,734 )
2013	2013	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	1/31/2013	NON-COMPETING CONTINUATION	$155,936
2013	2013	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	3	6/26/2013	NON-COMPETING CONTINUATION	$169,798
														Subtotal = $325,734

Issue Date FY: 2012 ( Subtotal = $346,525 )
2012	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	003	2	3/30/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$346,525
2012	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	002	2	3/29/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$346,525
2012	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	3/28/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$346,525
2012	2011	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	1	3/28/2012	NEW	$0
														Subtotal = $346,525

Issue Date FY: 2011 ( Subtotal = $391,345 )
2011	2011	JOHN WAYNE INSTITUTE FOR CANCER TREATMENT & RSCH	2200 SANTA MONICA BOULEVARD	SANTA MONICA	CA	90404	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	2/14/2011	NEW	$391,345
														Subtotal = $391,345

Grand Total All Awards = $3,803,405

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The Role of FOXCI in Basal-like Breast Cancer

Award Number: R01CA151610

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/14/2011

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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