NIH grant: TGF-Beta 3 in Mammary Involution and Post-Partum Breast Cancer (1R01CA318635-01)

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NIH grant 1R01CA318635-01: TGF-Beta 3 in Mammary Involution and Post-Partum Breast Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: John J Wysolmerski. Award: $539633.
Start: 2026-08-07T00:00:00.
PROJECT SUMMARY/ABSTRACT
Mammary gland involution is a dramatic example of coordinated cell death, allowing the mammary gland to
undergo repeated rounds of milk secretion during multiple cycles of reproduction. However, mammary
involution dramatically increases the lethality of pre-menopausal breast cancers occurring within 5 years after a
pregnancy. Thus, it is important to better understand the molecular mechanisms of mammary involution and
how they affect tumor progression and metastasis. Our premise is that, in response to milk stasis, an increase
in intracellular calcium induces the production of TGFE3 by mammary epithelial cells (MECs). In turn, we posit
that this cytokine triggers lysosome and mitochondrial dysfunction that interact to induce ROS production,
inflammasome activation, macrophage recruitment and cell death. We also hypothesize TGFE3 to be an
important mediator of tumor progression and metastases in post-partum breast cancer (PPBC). Preliminary
data suggest that TGFE3 contributes to lysosome expansion and dysfunction, changes in mitochondrial
function, and oxidative stress that trigger activation of the NLRP3 inflammasome and contribute to MEC death.
We plan to use BLG-Cre;TGFE3lox/lox (TGFE3-cKO) mice together with studies in cell lines to define how
lysosomes and mitochondria interact during early involution to cause cell death, activate inflammasomes and
recruit immune cells to the involuting gland. We will also use TGFE3-cKO mice to investigate whether TGFE3
promotes tumor progression and metastases in a model of post-partum breast cancer (PPBC). We propose 3
Specific Aims. Aim 1 will determine whether TGFE3 triggers lysosome dependent cell death (LDCD) during
early involution. We will use MECs and TGFE3-cKO mice to examine changes in intracellular calcium,
lysosome biogenesis, lysosome permeability, changes in the cellular transcriptome and cell death. Aim 2 will
determine whether TGFE3 causes mitochondrial dysfunction and inflammasome assembly during involution.
Aim 3 will determine whether TGFE3 increases metastases in a mouse model of PPBC. These studies will
better define the biology of early mammary involution to improve understanding of how cell death and tissue
remodeling are triggered and directly test the importance of TGFE3 to PPBC. Mice are necessary for this
research because no in vitro system recapitulates the complicated interplay between local and systemic factors
influencing mammary gland development and differentiation during pregnancy, milk production during lactation,
and coordinated cell death and tissue remodeling during involution. Furthermore, we will study how
inflammation, macrophages and TGFE3 affect the metastasis of spontaneously arising breast tumors in the
context of mammary gland involution. Many prior studies have validated the use of mouse systems to examine
the mechanisms of tumor progression during involution as a model of PPBC. This is an aggressive form of
breast cancer with significant mortality rates and the use of live animal models is justified to seek a better
understanding of the molecular mechanisms and potential new drug targets for women with PPBC.

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