Investigating the efficacy of g-Tocotrienol for the prevention of post-partum breast cancer

In the US alone, there was 3.7 million births in 2022. This number declined by 43% in women aged 15-24 since 2007 but increased in older women; 2% increase in women 35-39, 6% in women 40-44 and 12% in women 4549. Pregnancy at a younger age (< 25 year old) is associated with a reduction in breast cancer, while pregnancy starting after the age of 30 is associated with long-term (over 2 decades post-partum) increased risk, peaking at 6 years post-partum. Post-partum breast cancers (PPBC) are more metastatic compared to sub-type, size etc. matched breast cancers in never pregnant patients (NPBC). However, breastfeeding is generally protective against breast cancer but this is not the case for all women. Why lactation is protective in some women but not in others is unknown. The identification of mouse models where lactation is or is not protective respectively but where multiple variables (diet, frequency, length, number of pregnancies etc.) can be eliminated, may enable the identification of the mechanism. This application provides such models. At the sub-cellular level, lactation involves an exceptionally high level of secretion of proteins and synthesis of lipids. The endoplasmic reticulum (ER) is the entry point of the classical secretory pathway. The ER is in close physical contact with the mitochondria so that stress in the ER affects the mitochondria and vice versa. Our lab uses mice that share the same nuclear genome (C57BL/6) but have different mitochondrial genomes (C57 or NZB) (therefore referred to as BL/6C57 or BL/6NZB mice). Our model is relevant to humans as it recapitulates mitochondrial diversity observed in humans. We have characterized lactation in these mice and found that while the BL/6C57 females activates a potent pro-apoptotic stress response of the ER and mitochondria during lactation, these stress responses are transient and do not promote apoptosis in BL/6NZB females. Further, RNAseq data revealed an entirely different genes and pathways expression pattern during lactation. Importantly, these differences in gene expression levels translate in a pro- and anti-tumorigenic environment during lactation in the BL6/C57 and BL/6NZB females respectively. Bulk RNAseq and scRNAseq also revealed overlap of gene signatures between PPBC in humans and BL/6NZB lactating mammary gland and identified a PPBC-like population in BL/6NZB females during lactation. Since γ-Tocotrienol was reported to induced ER-mediated apoptosis, we treated BL/6NZB females late during lactation and found that it can reverse the pro-tumorigenic effect of lactation and PPBC formation. This finding raises the exciting possibility to use γ-Tocotrienol as a prevention strategy against PPBC. Therefore, our goal is to obtain data to support the design of a clinical trial for the prevention of PPBC through the following aims: Specific aim 1: Establish the most effective regimen of administration of γ-Tocotrienol for the prevention of PPBC. Specific aim 2: Investigate the protective effect of γ-Tocotrienol on late pregnancy in older mice. Specific aim 3: Deepening our understanding of the mechanism of action of γ-Tocotrienol on various cell types in the mammary gland.