Project 2
Mammary epithelial plasticity and
breast cancer progression
Cancer progression is fueled by acquired cell plasticity. For example, dysplastic cells may dedifferentiate into more primitive cell states and/or transdifferentiate into other cell types to generate malignant disease. Further, progression to metastasis and acquired therapy-resistance is often coupled with cell state transition toward more aggressive phenotypes. Despite a growing body of evidence linking cell plasticity to cancer mortality, there is a deficiency in therapies that can modulate cell plasticity and generate less aggressive disease. This is due, in part, to inadequate knowledge of the molecular regulators of plasticity. Thus, our lab is working to define regulators of cell plasticity and cell fate-switching processes in injured mammary epithelial cells, in pre-invasive ductal carcinoma in situ, and in triple-negative breast cancer (TNBC). Our overall goal is to develop therapeutic strategies for intercepting drivers of aggressive disease, ultimately improving patient outcomes
​
1. Chemotherapy-associated epithelial instability contribution to second primary breast cancer.
​Second primary breast cancer (SPBC) is becoming a major challenge for achieving long-term disease-free survival in breast cancer patients. SPBCs are independent tumors that arise in the breast of patients that have been diagnosed with a first primary breast cancer. While multiple tumors may occur synchronously in a patient, SPBCs are often diagnosed years after treatment and are associated with worse overall survival. The biological mechanisms driving SPBC remain poorly understood. Recently, cisplatin, a cytotoxic agent used to treat breast cancer, was shown to trigger basal-to-luminal transdifferentiation in the mammary gland and our studies demonstrate that luminal cells generated from transdifferentiation, e.g. “fate-switched luminal cells”, are epigenetically and transcriptomically distinct from homeostatic luminal cells. This project aims to test the hypothesis that therapy-induced basal-to-luminal cell fate switching generates a pool of unstable cells that are more susceptible to initiating SPBCs.
This project is led by Dr. Priyanga Jayakrishnan with support from Isabella Facchine. We are grateful for funding support from the MCW Cancer Center American Cancer Society Institutional Research Grant, and from Advancing a Healthier Wisconsin Postdoctoral Seed Grant (granted to Priyanga Jayakrishnan).
2. The role of the AP-1 transcription factor complex in luminal-to-basal fate switching.
Matched patient biopsies of TNBCs highlight non-genetic drivers of metastasis and therapy resistance, including a selection for basal-like and loss of luminal-like cancer cell states. These findings suggest that luminal differentiation therapies may represent an untapped approach for enhancing chemotherapy response or preventing disease progression. To define programs that may trigger loss of the basal state and gain of luminal, we performed transcriptomic and epigenetic analyses of cell states during mammary epithelial basal-to-luminal transition (BLT). Expression of AP-1 transcription factor complex members were dysregulated during transition, and AP-1 binding motifs were enriched in BLT-associated open chromatin regions, suggesting programs regulated by AP-1 may contribute to BLT. Pharmacologic inhibition of AP-1 locks mammary luminal cells in a luminal state. Further, AP-1 inhibition induces expression of the luminal gene GATA3 in human TNBC organoids and accelerates BLT. High expression of the key AP-1 subunit Jun has been linked to worse prognosis in patients with TNBC but not in patients with other breast cancer subtypes, suggesting AP-1 may activate programs that are unique to the aggressive nature of TNBC. Our overall objective for this project is to define molecular processes that induce luminal programs and determine the contribution AP-1 signaling in cell plasticity that contributes to TNBC initiation, metastasis, and therapy resistance.
This project is cooperatively led by Dr. Nikki Lytle and Dr. Priyanga Jayakrishnan, with support of Troy Biermann and Alex Eng. We are grateful for funding support from Advancing a Healthier Wisconsin Postdoctoral Seed Grant (granted to Priyanga Jayakrishnan).
​
3. The impact of obesity and menopause on mammary epithelial cell states and breast tumorigenesis.
Cell states influence transformation susceptibility and tumor subtype, which can be attributed, in part, to differences in epigenetic and transcriptional regulators of cell identity. Obesity and menopause are known risk factors for breast cancer, yet the impact of these conditions on mammary epithelial cell states remains understudied. We leveraged diet-induced models of obesity and a surgical-induced model of menopause to determine molecular and phenotypic changes that occur in mammary epithelium over time. Our studies reveal that obesity and menopause synergize to lead to expansion of the luminal progenitor (LP) population, which is thought to be the cell of origin for aggressive basal-like breast cancer. While LP cells normally only give rise to luminal cells in homeostatic conditions, LP from post-menopausal, obese mice are uniquely able to transdifferentiate to basal cells, suggesting that these cancer risk factors may contribute to tumorigenesis by enabling LP plasticity. Indeed, we show that obesity or menopause increases tumor susceptibility in situ and in transplant models in which LP cells serve as the cell of origin. To understand the molecular mechanisms by which obesity and menopause alter LP cell states, we performed single-nucleus ATAC sequencing. These data revealed substantial epigenetic reprogramming in LP cells isolated from both obese and post-menopausal mice, and enrichment of transcription factor binding sites in uniquely open DNA regions that are linked to breast tumorigenesis.
This project is cooperatively led by Dr. Nikki Lytle, Kai Liptow, and Dr. Priyanga Jayakrishnan, with support of Anooj Arkatkar (Michaela Patterson lab, MCW).