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Triple-Negative Breast Cancers Remodel Lipid Metabolism in Both Tumors and Surrounding Tissue
Triple-Negative Breast Cancers Remodel Lipid Metabolism in Both Tumors and Surrounding Tissue
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211153033
- ISBN
- 9798346877578
- DDC
- 574
- 서명/저자
- Triple-Negative Breast Cancers Remodel Lipid Metabolism in Both Tumors and Surrounding Tissue
- 발행사항
- [Sl] : University of California, San Francisco, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 166 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-06, Section: A.
- 주기사항
- Includes supplementary digital materials.
- 주기사항
- Advisor: Goga, Andrei.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2024.
- 초록/해제
- 요약Tumors display altered metabolism, often reflective of their microenvironment. In many cases including breast cancer, the invasive tumor front borders adipocytes. Reliance on mitochondrial fatty acid oxidation (FAO) has been observed in aggressive receptor 'triple-negative' breast cancers (TNBC), but the adaptations that permit elevated FAO, and the molecular mechanisms by which tumors coopt adjacent adipocytes for growth, remain elusive. The oncogene MYC dysregulates a range of cellular programs, including metabolism; MYC expression is elevated in most TNBC, and linked to increased FAO. To delineate alterations facilitating FAO in TNBC, I examined fatty acid binding proteins (FABP) thought to traffic FA to the mitochondria. Prior work identified FABP5 elevation in patient TNBC and a model of MYC-driven breast cancer. I observed increased FABP5 transcription in TN compared to 'receptor-positive' patient-derived cell lines, yet elevation across MYC-low and -high TNBC suggested levels are not solely MYC-regulated. Treating MYC-driven breast cancer cells with an FABP5/7 inhibitor caused lipid accumulation and impaired proliferation, but I found no growth defect after FABP5 knockout. While compensation by other FABPs may complicate knockout studies, specific inhibitors for FABP5 and other FAM targets are in clinical development. Despite evidence indicating reliance on FAO in TNBC, the source of FA fueling aggressive tumor growth is unclear. I next described a direct interaction linking cancer cell-adipocyte contact to tumor progression. Examining breast tumors and normal adjacent tissue from patient cohorts, patient-derived xenografts and mouse models, we observed activation of lipolysis and lipolytic signaling in neighboring adipose tissue. Using cancer cell adipocyte co-cultures, I found that functional gap junctions (GJ), small intercellular channels, form and permit cAMP transfer from breast cancer cells to adipocytes, activating lipolysis in a GJ-dependent manner. We identified connexin 31 (GJB3) as a promoter of in vivo TNBC growth and activation of adjacent lipolysis, or FA release. Our findings indicate a pro-tumorigenic role for direct tumor cell-adipocyte interactions. These studies reveal that TNBC dysregulate tumoral lipid metabolism and stimulate altered FAM in surrounding tissue.
- 일반주제명
- Cellular biology
- 일반주제명
- Oncology
- 일반주제명
- Molecular biology
- 일반주제명
- Womens studies
- 키워드
- Adipocyte
- 키워드
- Breast cancer
- 키워드
- Gap junction
- 키워드
- Lipolysis
- 기타저자
- University of California, San Francisco Biomedical Sciences
- 기본자료저록
- Dissertations Abstracts International. 86-06A.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211153033
■006m o d
■007cr#unu||||||||
■020 ▼a9798346877578
■035 ▼a(MiAaPQ)AAI31636856
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aWilliams, Jeremy LeBoff.▼0(orcid)0000-0002-2575-0188
■24510▼aTriple-Negative Breast Cancers Remodel Lipid Metabolism in Both Tumors and Surrounding Tissue
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a166 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-06, Section: A.
■500 ▼aIncludes supplementary digital materials.
■500 ▼aAdvisor: Goga, Andrei.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2024.
■520 ▼aTumors display altered metabolism, often reflective of their microenvironment. In many cases including breast cancer, the invasive tumor front borders adipocytes. Reliance on mitochondrial fatty acid oxidation (FAO) has been observed in aggressive receptor 'triple-negative' breast cancers (TNBC), but the adaptations that permit elevated FAO, and the molecular mechanisms by which tumors coopt adjacent adipocytes for growth, remain elusive. The oncogene MYC dysregulates a range of cellular programs, including metabolism; MYC expression is elevated in most TNBC, and linked to increased FAO. To delineate alterations facilitating FAO in TNBC, I examined fatty acid binding proteins (FABP) thought to traffic FA to the mitochondria. Prior work identified FABP5 elevation in patient TNBC and a model of MYC-driven breast cancer. I observed increased FABP5 transcription in TN compared to 'receptor-positive' patient-derived cell lines, yet elevation across MYC-low and -high TNBC suggested levels are not solely MYC-regulated. Treating MYC-driven breast cancer cells with an FABP5/7 inhibitor caused lipid accumulation and impaired proliferation, but I found no growth defect after FABP5 knockout. While compensation by other FABPs may complicate knockout studies, specific inhibitors for FABP5 and other FAM targets are in clinical development. Despite evidence indicating reliance on FAO in TNBC, the source of FA fueling aggressive tumor growth is unclear. I next described a direct interaction linking cancer cell-adipocyte contact to tumor progression. Examining breast tumors and normal adjacent tissue from patient cohorts, patient-derived xenografts and mouse models, we observed activation of lipolysis and lipolytic signaling in neighboring adipose tissue. Using cancer cell adipocyte co-cultures, I found that functional gap junctions (GJ), small intercellular channels, form and permit cAMP transfer from breast cancer cells to adipocytes, activating lipolysis in a GJ-dependent manner. We identified connexin 31 (GJB3) as a promoter of in vivo TNBC growth and activation of adjacent lipolysis, or FA release. Our findings indicate a pro-tumorigenic role for direct tumor cell-adipocyte interactions. These studies reveal that TNBC dysregulate tumoral lipid metabolism and stimulate altered FAM in surrounding tissue.
■590 ▼aSchool code: 0034.
■650 4▼aCellular biology
■650 4▼aOncology
■650 4▼aMolecular biology
■650 4▼aWomens studies
■653 ▼aAdipocyte
■653 ▼aBreast cancer
■653 ▼aGap junction
■653 ▼aLipolysis
■653 ▼aTriple-negative breast cancer
■653 ▼aBiomedical sciences
■690 ▼a0379
■690 ▼a0453
■690 ▼a0992
■690 ▼a0307
■71020▼aUniversity of California, San Francisco▼bBiomedical Sciences.
■7730 ▼tDissertations Abstracts International▼g86-06A.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17164702▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
